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Danish pharmaceutical giant Novo Nordisk launched its blockbuster weight-loss injectable semaglutide earlier this week, months after its competitor Eli Lilly’s tirzepatide hit Indian markets — and nearly four years after these GLP-1 therapies took the United States by storm.
The bottom line is this: these drugs have been shown to be extremely effective for weight-loss, helping people lose 15% to 20% of their body weight, equivalent to what they would otherwise lose with bariatric surgeries.
Additionally, they have been found to be effective or are being studied for a host of other conditions, including cardiovascular diseases, kidney disease, non-alcoholic fatty liver disease, and obstructive sleep apnoea. It has also been reported that people on these drugs end up making significant dietary changes, consuming smaller, healthier meals.
So how do these “miracle drugs” work? How were they discovered? And what are other benefits of these drugs?
Both semaglutide and tirzepatide belong to a new class of medicines called GLP-1 (glucagon-like peptide-1) receptor agonists. They are prescribed for the management of type-2 diabetes and obesity.
These drugs mimic certain naturally-occurring gut hormones called incretins (GLP-1 is one such incretin) produced in the small intestine, and are hence also known as incretin mimicker. They work by:
🔴 improving the secretion of insulin that allows more of the glucose in the bloodstream to enter cells where it can be used for energy;
🔴 inhibiting the secretion of the hormone glucagon that stimulates the liver to release stored glucose into the bloodstream;
🔴 slowing down the emptying of the stomach so that the glucose levels in the bloodstream doesn’t spike; and
🔴 reducing appetite by signalling to the brain that one is satiated.
Semaglutide and tirzepatide both mimic the action of GLP-1. Tirzepatide additionally also mimics the action of another hormone called glucose-dependent insulinotropic polypeptide (GIP).
While incretins were known as early as 1906, research into these gut hormones was overshadowed by the discovery of insulin in 1921. The substance produced by the pancreas has been used to manage diabetes for the past century.
Interest in incretins was renewed in the 1960s after several studies showed that oral intake of glucose led to more insulin secretion than intravenously given glucose — demonstrating that the gut makes hormones that regulate insulin and glucose levels. GLP-1 became the first incretin to be discovered in 1986.
Trials in the 1990s showed that GLP-1 infusion significantly increased insulin levels and lowered glucose levels in diabetic patients. But there was a problem: GLP-1 was not a very stable compound. This is where Novo Nordisk stepped in.
While the pharma giant was primarily looking for a diabetes therapy, researchers believed GLP-1 drugs could also be used to treat obesity given that transplantation of some glucagon-producing tumours in animals caused profound anorexia.
Novo Nordisk’s first GLP-1 medicine was the daily-injectable liraglutide. Trial participants, however, experienced severe nausea, and when the doses were reduced, the efficacy suffered. But the trials found that nausea could be somewhat mitigated by starting at a lower dose and then gradually titrating up — a method still followed for both semaglutide and tirzepatide.
The search for a once-weekly injectable eventually led to the discovery of semaglutide. This also proved to be much more effective than liraglutide for weight loss: those on semaglutide lost up to 15% of their body weight compared to 5% on liraglutide.
This led to further clinical trials to look into the drug’s weight loss effects. While it was already seeing off-label use for this purpose, semaglutide finally received approval for obesity management from the US regulator in 2021.
In addition to the 15% average weight loss, trials with semaglutide have demonstrated its ability to reduce the risk of major cardiovascular events (such as heart attacks and strokes) by 20%, and the risk of all-cause mortality by 19%. Studies have shown a 69% reduction in heart failure events.
There is also evidence that the drug can resolve fatty buildup in the liver in 63% of patients and improve liver fibrosis — the hardening of liver tissue due to fatty deposits — in 37% of cases.
Tirzepatide, which uses an additional target gastric inhibitory polypeptide (GIP), has been shown to lead to a weight-loss of up to 20% of the body weight. The medicine was also approved for the treatment of obesity-related obstructive sleep apnoea — a condition where a person’s breathing stops and starts while they sleep.
Trials have also shown that it can improve lipid profile, and demonstrated a 20% reduction in the risk of cardiovascular as well as all cause death.
“There is no doubt that the medicines are effective for kidney and heart conditions. There is also evidence that has emerged about fatty liver disease. But, what I am most excited about are the happy neurological side effects. There seems to be some evidence to show that the medicines are associated with lower risk of Alzheimer’s and other dementia,” Dr Ambrish Mithal, chairman of endocrinology and diabetes at Max Healthcare, told The Indian Express.
He added: “Importantly, these drugs have reduced cravings in people. They are not only eating smaller meals but also healthier ones. Sweet cravings have gone down. There is also evidence to show that it helps with alcohol addiction.”
Bolstered by the success of semaglutide and tirzepatide, several other drugs are now in the pipeline.
“There are a lot of drugs that are in the pipeline, including drugs with once-a-month dosing instead of every week and very effective oral pills,” Dr Mithal said.
Trials are ongoing for drugs such as retatrutide that uses three targets: GLP-1RA and GIP used by its predecessor tirzepatide along with glucagon.
There is also CagriSema that uses two targets GLP-1 RA and a new Amylin receptor agonist.
Oral GLP-1 drugs such as orforglipron and danulipron may soon be available as well. Two other drugs, which use two targets GLP-1 RA and glucagon — Survodutide and Mazdutide are also in phase 3 clinical trials.
