As overweight and obesity levels rise in populations the world over, they pose much more than cosmetic and mobility challenges to people. Body fat, especially visceral fat which is stored within the abdomen, is a factory that churns out an army of pro- and anti-inflammatory chemicals.
As visceral fat deposits rise, they release a flood of tissue-damaging pro-inflammatory chemicals, while reducing the production of anti-inflammatory chemicals like adiponectin. This chronic assault on body tissues increases the risk of cardiovascular diseases, diabetes, cancer and dementia.
Development and clinical deployment of several anti-obesity drugs has recently provided powerful interventions to reduce body weight and confer protection against the cardio-metabolic hazards associated with obesity. After years of limited success in providing effective medical treatments for obesity (beyond invasive surgical treatments), these drugs demonstrated dramatic results. A booming global market has emerged over the past few years, with clamour for these ‘miracle drugs’ going beyond clinical use to cosmetic transformation.
This was made possible by pathbreaking advances in biomedical research which helped to identify many hormones that are produced naturally by the body to regulate appetite, gastric motility and blood glucose levels, with brain signalling acting as a powerful communication tool to coordinate physiologic functions across a complex web of neuro-endocrine and metabolic pathways.
Among these, recently-discovered glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have emerged as key players besides well recognised hormones like insulin and glucagon. GLP-1 is a natural hormone produced mainly by the L-cells of the ileum (lower part of the small intestine). GIP, also known as gastric inhibitory polypeptide, is produced by the K-cells of the jejunum (upper part of the small intestine).
This surge in knowledge about the intricately designed and harmoniously coordinated human physiology enabled the development of drugs that may act as agonists (binding to a specific cell, producing a biological response mimicking a naturally occurring substance) of these hormones, to serve diverse clinical needs. At the forefront of this are the GLP-1 and GIP agonists (like semaglutide, liraglutide and tirzepatide). Apart from influencing insulin release and glucose homeostasis, these agents also have favourable effects on lipid metabolism and inflammation. GIP has also been recently shown to have a major influence on bone remodelling.
Euphoria about these miracle drugs has started dissipating in the last two years. While clinical trials are very good for demonstrating efficacy in sampled populations studied for a limited time period, adverse drug effects emerge more clearly over a longer time period when a large number of persons have started using the drug.
This has happened with the anti-obesity drugs. Initial reports reported gastrointestinal side effects (ranging from abdominal bloating due to delayed gastric emptying to disrupted intestinal muscle movement). While some initial reports of increased suicidal ideation have not been corroborated, anxiety and depression have been reported.
More serious adverse effects have emerged with increased global use. Sarcopenia, or loss of skeletal muscle, is a serious problem which can lead to falls. Apart from a direct action of the drugs on skeletal muscle, decreased appetite leads to low protein intake affecting muscle mass. Decrease in physical activity may also contribute. High-protein diets and protein supplements have been advocated to prevent or treat sarcopenia among users of GLP-1 agonists.
Over 22 percent of individuals using GLP-1 receptor agonists develop at least one nutrient deficiency within 12 months, driven by severe appetite suppression and delayed gastric emptying. Common deficiencies include vitamins D, B12, folate, thiamine, iron and calcium.
More disconcerting information has emerged from studies of persons who have discontinued the medication after using it for a prescribed period and losing weight. Studies showed that over 40-50 percent of lost weight was regained within 28-52 weeks of stopping. Some returned to their starting weight within 1.5 to 2 years. If that was disappointing, more disconcerting was the fact that benefits related to blood pressure, diabetes and blood lipid control dissipated fast after the drugs were stopped.
Researchers at Oxford University reviewed 37 studies with over 9,000 patients to compare the blockbuster weight-loss jabs with conventional dieting or other pills. The study found that individuals stopping GLP-1 weight-loss drugs regain weight about four times faster than those stopping traditional diet and exercise programmes. Patients typically regained most lost weight within two years, averaging 0.4-0.8 kg per month, with positive health indicators fading away in a year.
Reasons for this reversal could be many. When these drugs are given in larger than naturally produced hormones, without harmonising with the dietary fluctuations that occur over the usual course of a day, production of the natural hormone may be suppressed and may not readjust later. Exuberance over achieved weight loss may lead to dietary indiscretion in the belief that the ‘meds will take care of it’. Loss of skeletal muscle may lead to physical inactivity.
For young- and middle-aged persons who wish to use GLP-1 agonists to ‘look good’, there is a caution they must heed. While erectile dysfunction may improve alongside vascular function in elderly persons with diabetes, there is a 22 percent higher probability of developing that unwanted side effect among other males too. Among women users, the risk of inability to experience an orgasm is doubled. Ophthalmic complications of a serious nature have also been reported in a small proportion of users.
While dramatic weight loss and impressive metabolic gains have been demonstrated with these drugs, undesirable side effects and rebounds after discontinuation raise questions on their introduction into routine clinical practice. Amid those dilemmas, we must remember that GLP-1 agonists and GIP are natural hormones which nature has perfected for our bodies to produce and use.
Fruits like apples and guavas, nuts and seeds have been shown to increase their production and diets. Ultra-processed foods derange that capacity with adverse health effects. Perhaps it is best to promote healthy, wholesome traditional diets for the population, while reserving these drugs for clinical use in persons with extreme obesity or severe cardio-metabolic impairments of health.
K Srinath Reddy | Chancellor of the PHFI University of Public Health Sciences and Chair of the Centre for Universal Health Assurance at the Indian School of Public Policy
(Views are personal)
(ksrinath.reddy@phfi.org)