For the first time in human history, more people will die from obesity and its comorbid conditions (high blood pressure, type 2 diabetes, obstructive sleep apnea, etc) than famine. By 2030, an estimated half of the U.S. population will have obesity, with a disproportionate rise in those with severe obesity. By helping clients with sustainable weight loss, Restore Hyper Wellness aims to help them achieve the spirited and sustained energy needed to do more of what they love right now and the robust health needed to do what they love long into the future. But first, we should understand the background on obesity, adipose tissue and the rise of anti-obesity medications in treating sustainable weight loss.
As more research accumulates, we now understand obesity as a “chronic, relapsing, multifactorial, neurobehavioral disease” in which our brain becomes desensitized to normal appetite signals, making it more difficult to sense how much we’ve eaten and how much fat we have stored. Our lifestyle—primarily the quantity and quality of our food, movement, sleep, and stress—is certainly a primary driver. But our behaviors interact with and are influenced by our genetics, hormones, socioeconomic realities, and physical environment to determine our health status. On a molecular level, excess energy is likely an inciting factor, but culprits of weight gain also include systemic inflammation, hormone dysregulation, changes in the microbiome and even certain medications. This excess weight, particularly the visceral fat that surrounds the internal organs, fuels the inflammation that stokes chronic disease.
“Excess weight, particularly the visceral fat that surrounds the internal organs, fuels the inflammation that stokes chronic disease.”
What Is Fat?
When we try to shed the excess pounds—by aggressively dieting and exercising—our biology bucks based on its evolutionary adaptations. A normal amount of adipose tissue—what we call “fat”— is likely stored as a safeguard against famine and may provide the extra energy needed to survive the stress of life-threatening illness. This adipose tissue is an endocrine organ that releases and responds to hormonal signals to help regulate energy balance. When we lose weight, this triggers system-wide hormonal shifts, including a dramatic drop in leptin, the hormone that signals satiety or feelings of fullness. The decrease in leptin is matched by a concurrent increase in ghrelin, a hormone that signals hunger.
Thus, the brain reacts to forced weight loss by blunting fullness, intensifying the feeling of reward from food, and increasing cravings. It tells our muscles to burn fewer calories and to store extra calories as fat so the body can return to its previous weight or “set point.” This explains why weight loss diets are often short-lived and unsustainable.
Anti-obesity medication (AOM) or weight loss medications are pharmacological agents that reduce or control weight. When combined with changes to behavior, including healthy eating and increased physical activity, prescription medications help some people lose weight and maintain weight loss.
- On average, after 1 year, people who take prescription medications as part of a lifestyle program lose 3% to 12% more of their starting body weight than people in a lifestyle program who do not take medication.
- Research shows that some people taking prescription weight management medications lose 10% or more of their starting weight.
- Weight loss of 5% to 10% of starting body weight has been shown to contribute to cardiometabolic health by lowering blood sugar, blood pressure, and triglyceride levels.
- Losing weight also can improve some other health problems related to overweight and obesity, such as joint pain and sleep apnea. Most weight loss takes place within the first 6 months of starting the medication.
The Food and Drug Administration has approved the use of AOMs for individuals with either a body-mass index of at least 30 or a body-mass index of at least 27 with at least one weight-related comorbidity (i.e. hypertension, type 2 diabetes, sleep apnea, etc.)
Most recently, in AOM drug development, the focus has been on hormones like glucagon-like peptide 1, amylin, glucose-dependent insulinotropic peptide, and peptide tyrosine-tyrosine (PYY). These newly targeted peptides are intricately involved in appetite signaling and weight regulation and are secreted from the gut and pancreas.
Recent clinical trials have demonstrated superior weight loss results and safer side effect profiles than previous stimulant-based AOMs. This has ushered in a new and exciting wave of AOM drug development.
What is Glucagon-like Peptide 1?
Initially identified in 1987, glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid long peptide hormone mainly secreted by 3 tissues in the human body: the distal intestine, the pancreas, and the central nervous system. GLP-1 is known as an “incretin” which means that it decreases blood sugar levels in a glucose-dependent manner by enhancing the secretion of insulin, the hormone that helps your body regulate and use blood sugar for cellular energy.
GLP-1 primarily interacts with GLP-1 receptors (GLP-1R) to enhance insulin production and release. It also decreases glucagon secretion (which stops the body from releasing stored glucose from the liver) while increasing glucose uptake and glycogen synthesis in peripheral tissues. Finally, it delays gastric emptying and increases satiety or fullness.
GLP-1R is widely distributed in various tissues of the body including the lungs, kidneys, central nervous system, cardiovascular system, gastrointestinal tract, and skin and vagus nerve.
GLP-1 RA Therapy for Weight Loss
Higher dose GLP-1 RA therapy has also demonstrated another important metabolic benefit—weight loss. These agents delay gastric emptying, which makes patients feel fuller for longer. In addition, it seems they also act on appetite centers in the brain and gut to enhance satiety and reduce food cravings.
More recently, trials have explored the potential of semaglutide to promote weight loss. The STEP trials tested semaglutide at the higher dose of 2.4 mg/week (as compared to 1.0 mg/week for the original diabetes indication), specifically for promoting weight loss, regardless of the presence of type 2 diabetes.
- In STEP 1, in a population of people with obesity or overweight (and without diabetes), those who received semaglutide 2.4 mg plus a lifestyle intervention over 68 weeks lost an average of 14.9% in body weight as compared with just a 2.4% reduction in the placebo plus lifestyle intervention group.
- And in the STEP 3 trial, participants who received semaglutide 2.4 mg plus intensive behavioral therapy lost an average of 16.0% of their body weight (compared to 5.7% in the placebo group). Given these impressive findings, semaglutide has been hailed as a “game changer” in treating overweight and obesity.
- In June of 2021, the FDA approved the use of semaglutide (branded WeGovy) for weight loss alone, specifically for adults with a BMI of 27 mg/m2 with one or more weight-related comorbidities or in adults with a BMI of at least 30 kg/m2.
GLP-1 RA Plus Lifestyle Changes Equals Success
GLP-1 receptor agonists are analogues of natural hormones that stimulate the satiety pathway and improve the physiological response to food, which is dysregulated in obesity. These agents are a much safer and more sustainable option than previous AOMs, and hence, represent a major advance in our arsenal to combat obesity.
While we work to increase access to these medications for those who need them, we must keep front and center the fact that lifestyle change remains the centerpiece of sustainable weight loss. We must practice and design clinical protocols and programs accordingly.
Finally, given the robust weight loss effects of GLP-1 RA’s, we must refine our inclusion criteria and clinical protocols in order to safeguard and improve patients’ long-term health. Otherwise, we risk following our reflexive impulse that more of a good thing is even better. Let’s learn from recent precedents with other medications to understand and prevent the detrimental risks of such an overeager and misguided approach.
Restore’s Approach to Weight Management
GLP-1 RA therapy, currently with semaglutide and soon enough with tirzepatide and others in the pipeline, is extremely effective—for the right people. Our goal with the Restore Hyper Wellness Weight Management Program is to increase access to effective weight management medication, employ and evaluate rigorous clinical standards based on body composition, and provide education to empower supportive lifestyle behavioral changes.