With the recent clinical data and media hype around obesity medicines, we found ourselves looking closer at the disease, the history of weight loss medications, and the potential impact of effective weight management drugs on the healthcare system and even the global economy.
Obesity - More than a Lifestyle Issue
In the 2022 Nature Reviews article, Anti-Obesity Drug Discovery: Advances and Challenges, it is estimated that the global obesity prevalence has almost tripled since 1975, and 2/3’s of the US population has excess body weight, with over 1/3 of adults classified as Obese.
Obesity increases the incidence of numerous health conditions, including Type 2 Diabetes and Cardiovascular Disease. The condition also increases the risk of death from cancer of the esophagus, colon, rectum, liver, gallbladder, pancreas, and kidney. It is also associated with a 5-20 year decrease in life expectancy (depending on the amount of excess weight and number of co-morbidities)..
Obesity and related illnesses account for an estimated $190 billion in healthcare costs in the US every year. De-stigmatizing obesity by recognizing it as a genetically inheritable chronic, degenerative disease has helped increase behavioral and medical treatments available and increased the amount of medical and pharmaceutical research focused on weight management.
Weight Loss Treatments
Bariatric surgery is currently the most effective weight loss treatment and is associated with significant decreases in co-morbidities. However, these procedures cannot meet the huge need for weight management, so pharmacologic management of the condition is the most feasible option for mitigating the growing crisis.
The development of Obesity Medications has proved to be very challenging in the past. Pharmacologic agents are only now becoming effective because of the identification of many of the molecular pathways involved in controlling appetite (see graphic below).
Additional challenges to pharmaceutical development include the diverse nature of the patient population, the multiple neuroendocrine factors impacting weight loss/gain, imperfect animal models that don’t accurately predict results in humans, and the risk of safety issues associated with some of the medications.
An Abbreviated History of Pharmaceuticals & Obesity and Guidance for Treatment
Eric Coleman’s publication 1 May 2012 in Circulation. 2012;125:2156–2164 Food and Drug Administration's Obesity Drug Guidance Document-A Short History gives a helpful overview of FDA/Pharma work in early obesity drug development through 2012. I’ve highlighted some of the key points below:
In 1947, desoxyephedrine, or methamphetamine, was approved as a prescription obesity drug.
Over the next 25 years, amphetamine congeners (appetite suppressants) such as phentermine and fenfluramine were approved.
In 1973, the FDA, concerned about amphetamine abuse, limited the indication of all obesity drugs to short-term use (just a few weeks).
In 1985, it was recognized that obesity was a serious public health concern, and long-term studies were initiated with new and existing drugs.
In the early 1990s, with the discovery of Leptin as a hormone integral to body weight regulation, the oversight in the FDA moved from Neuropharma Drugs to the Metabolism and Endocrinology Division.
In 1995, there was an FDA AdCom to help drive the creation of a guidance document for obesity drug development.
The Draft Guidance was released in 1996 with the goal of facilitating the development of drugs to improve health and self-esteem by reducing body fat. The guidance recommended guidelines about BMI and comorbidities to be included in trials, along with endpoints and timelines.
Despite issues with some side effects and other risks, the FDA approved dexfenfluramine in 1996, sibutramine in 1997, and orlistat in 1999.
Due to CV side effects, dexfenfluramine and fenfluramine were removed from the market in 1997.
In 2007, Draft Obesity Guidance updated the guidelines to focus on medical weight loss – a long-term reduction in fat mass with a goal of reduced morbidity and mortality through quantifiable improvements in biomarkers such as blood pressure, lipids, and hemoglobin A1c
Rimonabant was a first-in-class cannabinoid type 1 receptor antagonist submitted to the FDA for approval. However, the neurological, anxiety, and depression symptoms caused the FDA AdCom to vote against approval, and the company withdrew the application. Approval was later withdrawn in the EU due to the serious psychiatric symptoms observed in patients using the drug.
Sibutramine was withdrawn from the US market in 2010 after the SCOUT trial results.
Current Guidance for the development of medical devices & drugs for weight loss/maintenance
I could not find a recent Guidance document from the FDA for pharmacological weight loss development, though there have been workshops and committee meetings to discuss the topic.
A draft guidance document for Medical Devices with Indications Associated with Weight Loss – Clinical Study and Benefit-Risk Considerations was recently published for comments, and the closing date is 14 Nov 2023.
The AGA – American Gastroenterology Association published guidelines in November of 2022: AGA Clinical Practice Guideline on Pharmacological Interventions for Adults with Obesity.
They state, “In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.” Further, “the panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap.”
Current Products Used in the US for Weight Loss
A mix of products are currently available for managing weight in the US. Some are explicitly approved for weight loss, such as:
Qsymia - phentermine and topiramate
Contrave - a fixed-dose combination of naltrexone and bupropion 2014
Saxenda - liraglutide SC
Wegovy - semaglutide SC
Note Belviq– lorcaserin, was withdrawn from the market in 2020 due to increased cancer risk.
Other pharmacologic agents are used off-label due to their “side effects” of causing weight loss. These include:
Mounjaro – tirzepatide
Trulicity – dulaglutide
Ozempic – semaglutide
Symlin – pramlintide
Topamax – topiramate
Wellbutrin – bupropion
Zonegran – zonisamide
Why So Much News About Weight Loss Drugs Now?
The introduction of the GLP-1-related drugs /drug candidates, incretin-based therapies, has significantly changed how obesity is regarded and discussed. The new mechanisms of action offer significant and meaningful benefits to patients. It is multifactorial, affecting the gut and brain, plus providing systemic improvements in insulin sensitivity for greater efficacy.
Data from studies of liraglutide and semaglutide in patients without T2D show that GLPR1R agonism improves metabolism and lowers body weight while also reducing Cardiovascular risk. Levels of weight loss seen in semaglutide studies are higher than previously thought possible and even safe. Over half of patients in the semaglutide study lost over 15% of body weight, and a third lost 20% of their body weight over the 68-week study period. Additionally, the SELECT trial showed semaglutide reduced the MACE-3 cardiovascular events by 20% vs placebo, a better than expected result.
The CV results move the products from being short term "aesthetic" drugs to products that save lives and help to change clinical management of diabetes and obesity, and hopefully improving access and reimbursement for broader use and a healthier population.
While the other products in the new class(es) are close behind Wegovy/Ozempic in terms of overall weight loss and perceived long-term health benefits - their trial outcomes for CV won't be available for 3-4 years. They will likely see a "halo effect" from the SELECT trial, but semaglutide is likely to remain in the spotlight for quite a while.
Follow-on products in development include oral formulations, triple receptor agonists, and targets in other parts of the metabolic cycle. See details here and here. We'll be keeping an eye on these as well.
Next Up - Eyes on the Potential Global Impacts of GLP1's and Successful Weight Management Agents.
Note: We relied on numerous publications for our summary, for detailed data and analysis please review the original sources below.
7. Endocrine Changes in Obesity - NIH endotext.org
Pharmatell - GLP-1 101 Top 10 Investor Questions on Diabetes Medications