**Updated November 11, 2023**

Recently, the FDA approved the Eli Lilly drug tirzepatide for weight loss (marketed as Zepbound™) that is currently approved for the treatment of type 2 diabetes (marketed as Mounjaro™).  Zepbound is the first and only approved treatment activating two incretin hormone receptors, GIP and GLP-1 to tackle an underlying cause of excess weight.  For more information on the science behind this emerging class of GLP-1 receptor agonists continue reading our previously published article from July of this year below.  

Originally published on July 28, 2023.

Bright green advertisements promoting a weekly weight loss drug, Wegovy, have taken over the subways of New York City. Ozempic graces the headlines with rumors of celebrities hosting Ozempic parties. The newest arrival, Mounjaro, garners social media’s attention, riding the wave of growing global popularity among recently FDA-approved drugs.

Originally designed for the treatment of type 2 diabetes, the GLP-1 receptor agonists Ozempic, Wegovy (both made by Novo Nordisk), and the combination drug, Mounjaro (made by Eli Lilly), have experienced shortages due to increased demand from customers seeking their potential benefits as weight loss medications. Obesity has become a global concern affecting approximately one-third of the world's population and is projected to surpass 50% by 2035. This increases the risk of various diseases, including coronary heart disease, high blood pressure, and type 2 diabetes. 

In response to this growing crisis, GLP-1 receptor agonists and their combined potential with GIP analogs and related therapies have emerged as promising treatment options for obesity and its related diseases. Understanding the differences between these scientific approaches and the future of weight loss will be critical as innovation in this field takes a new step forward.

How does the body process sugar and regulate blood glucose levels?

The body has a way of keeping blood sugar in balance. When the body’s blood sugar is low, the alpha cells in the pancreas make the hormone glucagon to notify the liver to make more sugar and release it into the bloodstream. When blood sugar is high, the beta cells in the pancreas produce insulin to help the body use or store the sugar in fat and muscle, as well as the liver and other body tissues. 

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), two hormones secreted from the intestines, are important in obesity and diabetes as they play crucial roles in regulating insulin production. Insulin is necessary as it keeps blood sugar levels in balance. When the body’s blood sugar is low, the alpha cells in the pancreas make the hormone glucagon to signal the liver to make more sugar. When blood sugar is high, the beta cells in the pancreas produce insulin to help the body use or store energy.

GIP stimulates the production of both insulin and glucagon and protects the insulin-producing cells from cell death while promoting their proliferation. GLP-1 stimulates insulin release from the pancreas while inhibiting glucagon release. 

How can obesity be managed by drugs?

To date, there are several types of drugs for managing both diabetes and obesity. GLP-1 receptor agonists, such as semaglutide (sold under the brand names Ozempic and Wegovy), activate the production of insulin by mimicking the actions of GLP-1. Tirzepatide (brand name Mounjaro) combines GLP-1 receptor agonists and GIP analogs. The GLP-1 receptor agonists bind to glucagon-like peptide-1 receptors in cells, while GIP analogs mimic the function of GIP, both stimulating the production of insulin. More recently, a new drug emerged, retatrutide, a GIP, GLP-1, and glucagon agonist with promising results in early clinical trials. 

Below is a summary of the drugs and GLP-1 receptor agonists being considered for weight loss.

    1.  GLP-1 receptor agonists such as semaglutide (Wegovy, Ozempic)

    2.  Combination approaches

           a.    GLP-1 and GIP receptor agonists such as tirzepatide (Mounjaro)

           b.    GLP-1, GIP, and glucagon receptor agonists such as retatrutide

The science behind these weight loss drugs

Activating GLP-1 and GIP receptors increases the body’s glucose and lipid metabolism. This reduces appetite and digestion rates while enhancing the ability to reduce adiposity and lower the risk of obesity-related diseases. Major effects include:

• Insulin secretion: GLP-1 and GIP can stimulate insulin release from pancreatic beta cells when blood sugar is high. This helps lower blood sugar levels. 
• Glucagon secretion: GLP-1 can inhibit glucagon release from pancreatic alpha cells when blood sugar is low. 
• Gastric emptying: GLP-1 and GIP can slow down the movement of food from the stomach to the intestine. This helps reduce appetite and calorie intake by making people feel full longer.  
• Appetite regulation: GLP-1 and GIP can affect brain regions that control hunger and satiety signals. This helps reduce appetite and food intake by making people feel less hungry and more satisfied.  

The importance of combination approaches 

A significant factor to consider in combination therapy is synergy. Synergy is when the effect of combining multiple drugs is greater than the sum of the individual effects of each drug. The importance of combining GLP-1 receptor agonists and GIP analogs in medication is that both molecular pathways are affected, rather than just one of the two primary hormones. In monotherapy drugs, such as semaglutides, it has been found in human and mouse trials that tolerance develops to some of the drug’s effects. Combination therapy helps prevent the body from building tolerance to the effects of drugs as multiple pathways are targeted. Another factor to consider in combination therapy is dosing. Combination drugs have the potential for smaller doses of each individual drug, therefore avoiding certain side effects.

What do clinical trials and real-world results look like? 

Several clinical trials have shown that GLP-1 receptor agonist drugs and GIP/GLP-1 receptor agonist combination drugs can cause significant weight loss in people with diabetes and/or obesity compared to placebo or other treatments.  

Notable studies published in The New England Journal of Medicine have highlighted the efficacy of semaglutide and tirzepatide. In a double-blind study involving 1961 participants, 2.4 mg of semaglutide, paired with diet and exercise, resulted in half of the participants losing 15% of their body weight, while one-third of participants lost 20% in a 68-week period. In contrast, the placebo group, which only made lifestyle changes, experienced a weight loss of 2.4%. In another study with 2539 participants, tirzepatide at doses of 5 mg, 10 mg, and 15 mg, combined with lifestyle interventions, led to a reduction in body weight of 25% or more for 15%, 32%, and 36% of participants, respectively. Only 1.5% of the lifestyle intervention group saw a reduction in body weight.

Studies comparing tirzepatide and semaglutide for patients with type 2 diabetes have shown tirzepatide was superior as 82 – 86% of patients on the medication had a decrease in the glycated hemoglobin level to less than 7% compared to the 79% of those on semaglutide.

Moreover, there seems to be a further noteworthy impact observed in drugs that combine targets such as GLP-1, GIP, and glucagon. Recent findings from Eli Lilly’s Phase 2 clinical trials reveal that individuals achieved an average weight loss of approximately 24%. If larger Phase 3 clinical trials substantiate these outcomes, it has the potential to significantly enhance Eli Lilly’s expanding portfolio of weight loss drugs. 

The popularity and impact of GLP-1 receptor agonists and GIP-based therapies

Ozempic, sensationalized by the media, has witnessed a surge in prescriptions in the United States. In the last year, Ozempic prescriptions have increased by 111%, and, since its approval in 2017, is the leading drug in the type 2 diabetes market (Figure 1). While primarily prescribed for type 2 diabetes, Ozempic has also been used for chronic weight management due to the shortage of Wegovy until 2023. 

Tirzepatide, approved in the United States in May 2022 under the brand name Mounjaro, contributed to Eli Lilly’s revenue of $537.6 million during the first quarter of 2023. As the medication receives U.S. FDA Fast Track designation for the treatment of obesity management, this drug is expected to compete alongside its semaglutide counterparts. 

Journal publication trends and patent analysis

A search in the CAS Content Collection for semaglutide-related publications showed that journals more than doubled between 2019 to 2022. Patents related to semaglutide have also increased, from 2 in 2011 to 109 in 2022. More publications are expected to arise as the popularity of semaglutides attracts more research, particularly in weight loss management.

Tirzepatide, being a newer drug, has seen fewer publications in the last decade according to the CAS Content Collection. However, there has been an increase in journal publications from 34 in 2021 to 72 in 2022. Patents related to tirzepatide have also increased during this period. As tirzepatide completes more trials and gains FDA approval for weight loss management, a surge of publications is expected. 

Pipeline analysis

The development of new drugs for diabetes and weight loss is an active area of research, with several promising candidates in various stages of clinical trials Novo Nordisk has oral semaglutide medications in its pipeline. OW ral semaglutide is still in Phase 1 and 25 mg and 50 mg semaglutide for diabetes management is in Phase 3. Additionally, there are ongoing Phase 2 trials for an oral GLP-1/GIP combination treatment for diabetes. Tirzepatide is currently in Phase 2 trials for nonalcoholic steatohepatitis (NASH) treatments and Phase 3 trials for heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea, morbidity and mortality in obesity, and cardiovascular outcomes. With its fast-track designation for chronic obesity treatment, tirzepatide is nearing regulatory approval. Eli Lilly also has a GIP/GLP coagonist peptide in Phase 1 trials for diabetes treatment.

Future landscape

As the prevalence of obesity and type 2 diabetes continues to rise globally, GLP-1 receptor agonists and GIP-based therapies show promise with an increase in publications and pipeline developments. Their success and impact can be seen in the increasing number of prescriptions and positive results reported in clinical trials. The next frontier in weight loss management will be in combination therapies including current medications like Mounjaro and early trials of retatrutide. By utilizing the body’s natural hormone responses, these medications not only provide a novel approach to weight loss and metabolic control but could lead to other disease treatments. To learn more about emerging therapeutics and key advancements, explore our in-depth Insight Reports on RNA therapeutics, exosomes, lipid nanoparticles, and more.  

In collaboration with Westlake University in Hangzhou, China, this CAS Insights Report highlights the emerging landscape of hydrogels, antimicrobials, lipid nanoparticles, exosomes, and more that are redefining the future of  biomaterials that interact with biological systems. This report identifies new opportunities, emerging trends, and key challenges ahead for the many industries and disciplines involved with biomaterials. Discover more in our detailed report below.

Throughout history, humans have been intrigued by the aging process and have attempted to understand and combat it. For example, ancient Chinese medicine included herbal remedies and acupuncture techniques designed to promote health and longevity. A key milestone came in the 1930s when it was discovered that caloric restriction enhanced lifespan in mice and rats. Further ground-breaking research in the 20th century explored the role of factors such as genetics and cellular senescence.

CAS has identified more than 500,000 scientific articles (mainly journal articles and patents) relating to aging physiology and anti-aging strategies. There has been a steady growth in these articles over time, with research efforts intensifying in the last decade (Figure 1).

The trend in anti-aging research is showing no signs of slowing down. The World Health Organization (WHO) estimates that by 2050, the world’s population of people aged 60 years and older will exceed 2 billion. This demographic shift towards an older population has spurred increased interest and investment in anti-aging research to address age-related diseases and promote healthy aging. The United Nations (UN) General Assembly declared 2021–2030 the UN Decade of Healthy Ageing, a program promoting global collaboration to find interventions that can extend health span and improve quality of life for older individuals.

While aging is a risk factor for many chronic diseases, there is interest in promoting "successful aging" by focusing on overall health and wellbeing. In this article, we delve into the aging process, exploring a diverse range of interventions aimed at promoting successful aging and longevity. Which of these anti-aging treatment strategies hold the most promise for promoting successful aging?

Aging: Not just skin deep

The term "anti-aging" often evokes thoughts of visible signs of skin aging like wrinkles and sagging. Skin aging is extensively studied due to its social and psychological impacts. As the body's largest organ, the skin plays a vital protective role against environmental factors. With age, the skin's ability to fulfill this function can diminish, affecting overall health. Although skin aging is a natural process, measures can be taken to slow it and maintain skin health. The cosmetics and skincare industries, including companies like L'Oreal and Amorepacific, have a significant interest in this area, holding numerous patents in the field. These products feature ingredients like hyaluronic acid or vitamin E, which affect the surface layers of the skin.

The process of aging is far more complex than what we see on the surface. Aging is broadly defined as a gradual functional decline in a living organism’s intrinsic ability to defend, maintain, and repair itself to keep working efficiently. The brain is particularly sensitive to the effects of aging, causing changes in its size, vasculature, and cognition. This puts us at increased risk of developing certain neurological disorders as we age such as Alzheimer’s disease.

Aging is also characterized by a gradual loss of physiological fitness that affects the entire body, leading to deteriorated functions and enhanced vulnerability. Although aging alone is not the direct cause of serious ailments like cancer, diabetes, and cardiovascular disorders, it serves as a significant risk factor for these conditions and numerous others. Consequently, the recognition of this connection has brought the rapidly growing field of aging research to the forefront.

The hallmarks of aging

Aging is essentially the accumulation of damage over time, leading to specific physiological changes known as the hallmarks of aging. In 2013, nine molecular and cellular hallmarks of aging were defined, providing a framework for future research. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication (Figure 2).

To complicate matters further, the different hallmarks of aging are interconnected and can contribute to each other (Figure 3). In fact, these hallmarks are so intertwined that some researchers propose that we should instead consider aging as a process that operates in four layers, each at a different biological scale. However, as we consider aging, it’s clear that understanding the relationships between these different hallmarks can help in developing effective interventions to prevent or treat age-related diseases.  

What are the most promising anti-aging treatment strategies?

A variety of anti-aging treatment strategies targeting the hallmarks of aging have been explored, many of which have been targeted to multiple hallmarks (Figure 4). Here’s an overview of five such interventions, and the current evidence for each approach to determine which of them hold the most potential.

Physical exercise exhibits a significant anti-aging impact at a cellular level, related to each and every aging hallmark. Research on physical exercise as an intervention for aging indications is well established and clinical trials are seeing promising results. Notable ongoing trials are exploring the effects of physical exercise on Alzheimer’s disease, unsteady gait, cognitive function, and post-traumatic stress disorder (Table 1).

Dietary intervention as anti-aging strategy

Recently, two related dietary interventions, caloric restriction and intermittent fasting, have been reported to effectively prolong the healthy lifetime of the nervous system by affecting basic metabolic and cellular signaling pathways that regulate longevity. Although this approach has proven successful in animal models, caloric restriction is a difficult strategy to apply in humans, as it requires a high level of determination and self-control. An alternative route is to emulate its effects using ‘caloric restriction mimetics’. Like physical exercise, caloric restriction is a well-researched anti-aging treatment strategy with several clinical trials currently underway (Table 2).  

Metabolic manipulation as an anti-aging strategy

The mammalian target of rapamycin (mTOR) signaling pathway has been identified as a significant participant in cellular metabolism that associates nutrient sensing with critical cellular processes that energize cell growth and proliferation. mTOR inhibition with agents such as rapamycin is widely explored in anti-aging clinical trials in a range of indications from aging frailty to age-related sarcopenia (Table 3). 

Senotherapy as an anti-aging strategy

Senotherapy involves the development of potential therapeutic agents and approaches to explicitly target cellular senescence, a condition associated with aging and age-associated pathologies. Researchers are investigating several senotherapeutic strategies. A particularly exciting pharmacological strategy is the use of senolytics, which are small molecules that can selectively eliminate senescent cells that are causative of multiple age-related disorders. Targeting aging cells in this way is already being evaluated in clinical trials (Table 4).

Cellular reprogramming as an anti-aging strategy

Is it possible to turn back the clock at a cellular level? Cellular reprogramming aims to do exactly this by converting terminally differentiated mature cells into induced pluripotent stem cells. By reprogramming cells in this way, we can effectively ameliorate several hallmarks of aging such as mitochondrial dysfunction, telomere attrition, changes in epigenetic alterations, genomic instability, and senescence. Though research is still in the early stages, this approach has shown promise in preclinical models. 

By tackling the challenges of an aging population head-on, anti-aging research holds the promise of transforming the way we age, enhancing our overall wellbeing, and fostering a healthier and more vibrant global community.

To learn more about the exciting and dynamic field of anti-aging research, read our latest journal manuscript here.