Obesity drugs: What are they, and do they work?

Take-home points

• New obesity drugs effectively reduce body weight by reducing hunger and the desire to eat.
• Medication is not a replacement for lifestyle change; it is a biological aid to make weight loss efforts easier to maintain.
• Only semaglutide has been approved by the FDA to treat obesity.
• Side effects are manageable for most people, and the weight loss from medication seems to reduce the risk of long-term chronic disease.

Rates of obesity rising

Roughly two-thirds of adults with obesity attempt to lose weight every year while obesity rates continue to rise globally.¹ Even the most scientifically backed lifestyle regimes struggle to cause more than 5% body weight loss in the long-term.^{2, 3} So why is this?

First, as outlined in a previous article about what causes obesity, the main driver of obesity is the environment. Obesity is not necessarily the result of low personal effort; people who are struggling do not control the central issue. Highly processed and cheap calorie-dense foods dominate the food supply; advertising and marketing campaigns normalise eating these foods, and many people lack the access and finances to prioritise healthier food choices.  

Second, body fatness is not just the haphazard result of how much we ‘choose’ to eat and exercise—rather, the brain actively regulates body fat with strong genetic influences.^{4, 5} Similar to how a thermostat responds to changes in temperature, scientists consider the human brain to “defend” our current waistline and unconsciously fight against weight loss efforts: as soon as the pounds come off, hunger goes up,⁶ calorie burning drops,⁷ and calorie-rich foods become more appealing.⁸

One scientific breakthrough in the last decade has been identifying over 1000 genes that, in an obesity-promoting environment, make some people more susceptible to weight gain than others. Most obesity-related genes directly affect the brain, influencing appetite regulation, the sense of food reward in response to eating, and the internal cues that make us stop eating and remain full. Quite simply, these genes are more active in people living with obesity.⁴ Because of this, even if, hypothetically, everyone had the same motivation and willpower to live a healthy lifestyle, body fat levels would differ substantially from one person to another due to biology alone.  

Who are obesity drugs for?

Obesity drugs are intended for use by all adults living with obesity. The distribution and prescription of these drugs will be no different than drugs used to treat other chronic diseases such as heart disease and type 2 diabetes. If you have obesity and want to explore your treatment options (surgical, medical, and lifestyle-based), your doctor should be open to a clinical discussion and assessment.

How do obesity drugs work?

Failed weight loss pills litter the history of medicine. Not failing because they did not cause weight loss per se, but failing because the lost weight was mostly the product of severe and often dangerous side effects. Some medications increased heat production so much that it replicated burning from the inside out, for example, while others reduced fat absorption to the point that chronic diarrhoea was almost inevitable.  

However, years of rigorous scientific investigation have produced new obesity drugs that are not only as effective, if not more so, but act via mechanisms that most people find less intensive. The FDA-approved obesity drug semaglutide, for instance, does not affect your fat metabolism or make you excrete more of the food you eat; rather, it affects the brain. Semaglutide targets the unconscious regions of the brain (the brainstem and hypothalamus) which typically make weight loss difficult to maintain: the brain’s perceived need for calories (hunger) and its tendency to be seduced by food even when we do not feel hungry (reward).⁹  Therefore, in what might sound like a timely breath of fresh air to yo-yo dieters or those struggling with their weight, obesity drugs make it easier to ‘diet’.  

‍Are new obesity drugs effective?

Yes. The highest quality research to date clearly shows the weight loss-inducing effect of new obesity drugs. As a result of their actions in the brain, new obesity drugs reduce food intake in people with obesity.^{10, 11} People are more likely to experience being part-way through a meal and be satisfied without finishing or adding more food.

Further, high-quality research suggests that semaglutide causes food cravings to fade quite substantially.^{10, 11} The cravings for calorie-dense food (cakes, cookies, baked goods, etc.) become weaker and easier to ignore.

When weight loss is measured directly, it is no exaggeration to describe the latest study results as ground-breaking. The STEP-1¹² and STEP-4¹³ trials, published last year, report that semaglutide, alongside intensive lifestyle changes, caused overweight participants to lose an average of 15 - 18% of their body weight over 68 weeks. That would mean a patient weighing 90 kg (200lbs) can expect to weigh 74–77 kg (164-170lbs) in just over a year by choosing to take semaglutide as part of their obesity treatment. To put this into perspective, participants who lost weight with only the intensive lifestyle changes struggled to lose even half this.  

‍

^{‍Image taken from the Step-4 trial publication.}

Consider, too, that we expect weight recurrence following lifestyle changes due to regulatory systems in the brain–hence why the average person gains back 80% of lost weight within 5 years of dieting.¹⁴ On the other hand, for as long as a patient continues medication, weight loss from obesity drugs is sustained. As is the case for most drugs that treat chronic diseases (such as blood pressure or cholesterol-lowering medications), continual benefit requires continual use. This being said, there still appears to be marginal long-term weight loss even when semaglutide medication is stopped (approx. 5% loss in body weight). Most, but not all, of the lost weight will creep back on.

Are obesity drugs safe?

To date, only semaglutide medication has been approved for disease treatment. In 2017¹⁵ and 2018,¹⁶ the US Food and Drug Administration, the European Medicines Agency, and Health Canada all approved its use for treating type 2 diabetes. In 2021,¹⁷ the FDA also approved semaglutide to treat obesity. Similar obesity drugs, such as tirzapetide, are still under clinical investigation and have not yet been approved to treat obesity.

There are potential side effects of semaglutide (including nausea, constipation, and heartburn), but trials report that few people stop taking the drug due to side effects.¹² The reported side effects are also often mild and short-lived if the medical dose starts low and increases gradually.

In terms of long-term health impacts, new obesity drugs appear largely positive overall. If there are concerning long-term side effects, researchers are yet to find them. Or, the benefits of weight loss offset any drug detriment. The Pioneer-6¹⁸ and Sustain-6¹⁹ trials showed that semaglutide reduces major cardiovascular events by 21 - 24% in patients with type 2 diabetes, comparable to the effect of cholesterol-lowering drugs.²⁰ When researchers pool the data from these trials and others, semaglutide and other obesity drugs also reduce the risk of dying by 12% in patients with type 2 diabetes.²¹

Join the conversation on the TRTed Community

‍

References

1. Martin CB et al. NCHS Data Brief. 2018;(313):1-8.

2. Knowler WC et al. N Engl J Med. 2002;346(6):393-403.

3. Hall KD & Kahan S. Med Clin North Am. 2019; 102(1): 183-197

4. Schwartz MW et al. Endrocr Rev. 2017;38(4):267-296.

5. Elks CE et al. Front Endocrinol (Lausanne). 2012;28;3:29.

6. Kissileff et al. Am J Clin Nutr. 2012;95(2):309-17.

7. Leibel RL et al. N Engl J Med. 1995;332(10):621-8.

8. Rosenbaum M et al. J Clin Invest. 2008;118(7):2583-91

9. Secher A et al. J Clin Invest. 2014;124(10):4473-88.

10. Friedrichsen M et al. Diabetes Obes Metab. 2021;23(3):754-762.

11. Blundell J et al. Diabetes Obes Metab. 2017;19(9):1242-1251.

12. Wilding J et al. N Engl J Med. 2021;384:989-1002

13. Rubino D et al. N Engl J Med. 2021;325(14):1414-1425.

14. Anderson JW, et al. Am J Clin Nutr.2020;74(5):579–84

15. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000TOC.cfm

16. https://www.ema.europa.eu/en/medicines/human/EPAR/ozempic

17. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014

18. Husain M et al. N Engl J Med. 2019;381(9):841-851.

19. Marso SP et al. N Engl J Med. 2016;375(19):1834-1844.

20. Kearney PM et al. Lancet. 2008;371(9607):117-25.

21. Kristensen SL et al. Lancet Diabetes Endocrinol. 2019;7(10):776-785.

‍