The Data For Weight Loss Medications Just Keeps Pouring In.
Why the weight loss medications known as incretins are turning point in medical history.
“There are decades where nothing happens; and there are weeks where decades happen.”
Vladimir Ilyich Lenin.
It always feels strange to quote Lenin, but when it comes to weight loss medications, it is hard not to feel that decades are happening right before our eyes.
For over 50 years, rates of those who are overweight or obese have been rising rapidly.
The reasons for this enormous increase are multifactorial and largely driven by our highly obesogenic environment.
But just because we know this fact hasn’t made the impact we would have hoped for.
Recent research suggested that the weight loss market was estimated to be worth $224 billion annually in 2021 and is estimated to exceed $400 billion by 20241.
Despite the rise in obesity rates, the growing recognition of it as a global problem and the astronomical sums of money we spend on addressing it, the tide continues to rise.
That is until now.
In 2021, the weight loss medication Semaglutide, which you probably know as Ozempic, was approved for the management of excess weight-causing health issues.
This was on the basis of several studies demonstrating weight loss of approximately 15% over about one year2.
Then the dam broke.
Multiple versions of this medication class, known as incretins, have been tested, all demonstrating reductions in weight we had never seen before, with the exception of that achieved with bariatric surgery3.
With all of this in mind, we have to always remember ‘why’ we are concerned about excess weight and obesity.
The reason excess weight is such big issues are the health consequences it confers with increased rates of diabetes, heart disease, osteoarthritis, obstructive sleep apnea, non-alcoholic fatty liver disease and others, just to name a few.
Sure, many people want to lose weight for aesthetic purposes, but the real reason why incretin-based therapies have such value is the subsequent reduction in the health consequences that come with them.
This is where ‘Decades’ are happening.
In addition to substantial weight reductions here is what is happening to other disease states.
Osteoarthritis.
Globally, over half a billion people suffer from osteoarthritis4.
Although not generally considered a condition that can kill you, it can certainly impact your quality of life and limit the activities you do on a daily basis.
While joint replacement surgeries are effective in this space it would be preferable if surgical interventions could be avoided.
Patients with osteoarthritis who are also obese and who are treated with semaglutide experience a significant reduction in pain scores related to osteoarthritis5.
They also lost, on average, 13kg in weight after about one year of treatment.
Obstructive Sleep Apnea.
Imagine someone sneaking into your room every night and choking you to the point where your oxygen levels drop significantly, and in the morning, you do not recall the event.
Now imagine that happening over 30 times.
Every hour.
That is severe obstructive sleep apnea (OSA), and with that serious interruption to sleep quality also comes a doubling in the risk of future heart disease, particularly stroke6.
Weight reduction is the first-line approach to managing most patients with obstructive sleep apnea.
When patients with OSA and obesity are treated tirzepatide, a novel GLP1 and GIP inhibitor, they lose approximately 18kg in weight.
With that significant weight reduction also comes a significant reduction in sleep apnea scores known as the Apnoea Hypoxia Index7.
Non Alcoholic Fatty Liver Disease.
There are various stages of nonalcoholic fatty liver disease, which is more recently known as MAFLD - Metabolic dysfunction-associated fatty liver disease.
These stages can range from mild fatty liver infiltration to serious scarring and fibrosis terminating in liver cirrhosis and potentially liver cancer.
What happens when you treat patients with MAFLD with newer weight loss therapies such as tirzepatide and retatrutide?
As expected, you see serious improvements in liver markers.
In those with MASH (i.e. fibrosis diagnosed with a liver biopsy), treatment with tirzepatide resulted in significant weight reductions but also large improvements in markers of liver fibrosis8.
In those with the less severe MAFLD, treatement with retatrutide resulted in 86% redutions in liver fat with almost 95% of patients having less than 5% liver fat at close to 1 year9.
Visceral fat levels also fell by close to 50%.
Outside of bariatric surgery we have never seen such incredible results.
Type 2 Diabetes
When it comes to the increasing the risk of major chronic diseases such as cardiovascular disease, many cancers and dementia, type 2 diabetes plays a huge role.
Avoiding diabetes and its precursor states inclduing insulin resistance is key.
For example, people with type 2 diabetes are 10 times more likely to develop cardiovascular disease than those who do not have diabetes10.
Developing type 2 diabetes early in life, particularly at ages less than 40 can shorten your life by up to 16 years11.
As a risk factor for cardiovascular disease and many of the major chronic diseases that result in an early death, avoiding type 2 diabetes is key.
The question is how do weight loss therapies fare at such an endevour?
The answer is…. eye wateringly well.
In those with obesity treated with tirzepatide the incidence of type 2 diabetes was reduced by a whopping 93% at less than 2 years12.
This is in a population of people in which 40% already had pre-diabetes and, therefore, a very high probability of of progressing to full type 2 diabetes.
Treating Diseases Or Just A Side Effect Of Weight Loss?
The real question in all of these studies is whether there is something magical about incretin-based therapies for these conditions or whether the improvements we see are simply a function of weight reduction.
We cannot say for certain, but my guess is that most, if not all, of the effects result from weight reduction alone.
Which should come as no surprise.
They still work, though, and that is what matters to me.
In an ideal world, we would have our environment set up in such a way that incentivised us to do the things that minimised the risk of excess weight and all the health-related complications that come with it.
But we don’t live in that world.
Hopefully, the future will tilt more in that direction.
But for now, we are facing a tsunami of excess weight and health-related complications.
Weight loss therapies, broadly known as incretin-based therapies, now offer us a way to minimise the impact of excess weight and obesity.
These tools are not without risks, just the same as any other medication, and cost continues to be an issue.
However, they are a tool that continues to demonstrate incredible utility.
We should not be afraid to use them.
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Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021; 384:989-1002
Incretin-based therapies for the treatment of obesity-related diseases. npj Metab Health Dis 2, 31 (2024).
GBD 2021 Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023 Aug 21;5(9):e508-e522.
STEP 9 Study Group. Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis. N Engl J Med. 2024 Oct 31;391(17):1573-1583.
Obstructive Sleep Apnea and Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation. 2021 Jul 20;144(3):e56-e67.
SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med. 2024 Jun 21.
SYNERGY-NASH Investigators. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024 Jun 8.
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med (2024).
Association of lipid, inflammatory, and metabolic biomarkers with age at onset for incident coronary heart disease in women. JAMA Cardiol 2021;6:437–47
Emerging Risk Factors Collaboration. Life expectancy associated with different ages at diagnosis of type 2 diabetes in high-income countries: 23 million person-years of observation. Lancet Diabetes Endocrinol. 2023 Oct;11(10):731-742.
Tirzepatide for Obesity Treatment and Diabetes Prevention. NEJM Nov 13 2024
Thank you for describing the benefits of using these weight loss drugs. I am very concerned however that you didn’t give your readers a full picture of these drugs. An intelligent decision to use them can’t be made without also understanding the possible downsides. You made no mention of intestinal paralysis, retinopathy, gall bladder disfunction or any of the other possible side effects. I have several friends using these drugs and 3 of them were admitted to the hospital because they suffered from one of these issues. Please be responsible and tell the whole story so patients can weigh their options.
Not arguing but see Bonnie’s comment above. Exercising caution for long term, even lifetime use is important.