Navigating the -tides: Medication-Assisted Weight Loss on the Forefront

We are in the midst of a public health catastrophe. 

Nearly 2 out of every 3 Americans are overweight or obese. 

Whether you struggle with excess body fat yourself or care deeply for someone who does, the conclusion is the same… we desperately need an intervention. 

In light of the current obesity epidemic, it’s no surprise that weight-loss medications such as Ozempic (semaglutide) continue to break headlines. The recent popularity of these medications emerges from a dire need to combat staggering rates of obesity and metabolic dysfunction. Despite only recently attaining household name status, the history of these medicines extends well into the past. 

In order to better understand the present and envision a healthier future, let’s dive into the past.

Risky Beginnings: Early Weight-Loss Medications

First-generation weight-loss medications fell out of favor fairly quickly, for good reason. One of the first pharmaceutical weight-loss treatments, 2,4-Dinitrophenol (DNP) was previously used to make explosives and sulfur dyes. Clinical applications were considered following the observation that factory workers exposed to DNP lost weight rapidly. A harsh reality that may have been overlooked was that DNP also resulted in a multitude of workplace injuries and fatalities. DNP modulates mitochondrial metabolism via oxidative phosphorylation uncoupling, which substantially increases metabolic rate and body temperature. DNP was banned shortly after it was introduced into clinical practice due to significant toxicity and risk of death. 

Roughly around the same time, Japanese chemists extracted bioactive Ephedrine from the ephedra plant, which had been used in traditional Chinese medicine for thousands of years. Through trial and error, Ephedrine was transformed into Methamphetamine. As a potent central nervous system stimulant, Methamphetamine accelerates energy expenditure while simultaneously suppressing appetite. Methamphetamine was reclassified as a controlled substance after its highly addictive nature and toxicity were elucidated. 

Early research and development into weight-loss drugs focused on the drastic escalation of energy expenditure. This paradigm isn’t entirely misguided but context is critical. Obesity is primarily a result of sustained energy imbalance. But cars would be impractical and unsafe without a brake pedal. Unhindered acceleration will inevitably result in a collision.  

The Power of Incretins in Metabolic Health

Additional pathways and therapeutic targets were on the radar during the stimulant-centric era of drug development. Scientists have spent more than a century exploring the gut hormone axis and its impact on metabolism. The discovery of incretin hormones in the late 20th century lay claim as one of the most groundbreaking breakthroughs in our understanding of metabolism. Researchers uncovered a distinct insulinotropic response from orally administered glucose as opposed to IV glucose, leading them to recognize the hormonal impact of digestion itself. 

Incretins are secreted by the GI tract after nutrient intake to stimulate the release of insulin. Incretin signaling pathways are essential to maintain glucose homeostasis. Within minutes of food ingestion, incretins reach pancreatic beta-cells priming them for insulin release. The incretin effect is akin to tidying up a spare bedroom in anticipation of an unexpected guest. 

This incretin effect is impaired in the context of metabolic disease. Pancreatic beta cell dysfunction results in suboptimal response to incretins and poor downstream insulin secretion. In most cases, beta-cell dysregulation emerges in tandem with resistance to insulin itself, forging a double-edged sword of metabolic pathogenesis. 

If unidentified or left untreated, the pre-diabetic state rapidly deteriorates into full-blown diabetes. CDC and ADA statistics paint the following picture:  

• More than 1 in 3 Americans are pre-diabetic 

• 80% of them don’t know they are 

• 1 in 2 of them will develop diabetes within 5-10 years 

To recap what we’ve discussed so far: Incretin hormones regulate the insulin response to food and their ability to do so is contingent on beta-cell activity and insulin sensitivity, both of which are impaired in metabolic disease. Let’s zoom in a bit more. 

The primary incretin hormones are Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). Released by the gut in response to food, they stimulate the pancreas to release insulin and inhibit glucagon production. If blood sugar levels are the speed at which your car travels, glucagon is the accelerator and insulin is the brake. Insulin decreases blood glucose levels by increasing cellular uptake and glucose storage in the liver. Glucagon releases stored glycogen in the liver as glucose. Both work in tandem to ensure your physiological car continues onward without exceeding the metabolic speed limit. 

Natural GLP-1 vs GLP-1 Receptor Agonists

Incretin pathways quickly captured the attention of clinicians and drug developers as a novel therapeutic target for metabolic dysfunction. Endogenous or native GLP-1 has a rapid half-life of about 2 minutes thanks to rapid degradation by the enzymes dipeptidyl-peptidase-4 (DPP4) and neutral endopeptidase (NEP). 

If you’re new to pharmacology, let’s break down the basics. We have two primary players known as ligands and receptors. The ligand is the key, and the receptor is the lock. Ligands bind to their designated receptor in order to trigger a physiological response. For example, insulin is one ligand of the insulin receptor or IR. Insulin binds to the IR to promote the cellular uptake of glucose and other nutrients. 

Ligands that bind to their designated receptor to exert a biological response are agonists. 

Ligands that bind to the same receptor site and block an agonist from exerting its effect are known as antagonists.  

The compatibility between a ligand and its receptor is known as affinity. 

For example: Many prescription painkillers and street drugs are opiate agonists as they bind to the opioid receptor. In cases of overdose, a medication known as Naloxone (Narcan) is routinely administered due to its ability to act as an opioid antagonist. Naloxone has a greater affinity for the opioid receptor than drugs like morphine, oxycodone, and fentanyl. Therefore, it blocks or inhibits these medications from continuing to exert their effects. 

In recognizing that native incretin hormones like GLP1 metabolize quickly due to enzymatic breakdown, researchers began to develop a new class of degradation-resistant medicines aimed at binding to the GLP1 receptor. 

The first GLP-1 receptor agonist, Exenatide, was FDA-approved for the treatment of type-2 diabetes in 2005. At their core, GLP-1 receptor agonists are incretin mimetics. They aim to restore the powerful incretin effect, improving the post-meal (postprandial) insulin response to enhance blood glucose control. Additionally, Exenatide was shown to attenuate pancreatic glucagon release, putting a guardrail around excessive blood glucose production after eating.  For additional context, Hba1c, fasting insulin, and fasting blood glucose, are the main biomarkers used to gauge metabolic status and clinical efficacy.

Exenatide paved the way for future research as a common ancestor spawning the development of more effective medications to target this pathway. Continued investigation into Exenatide uncovered some subtle but groundbreaking effects: 

• Delaying of gastric emptying, meaning food spends more time in the GI tract allowing for more stable digestion and meal-derived glucose response 

• Prolonged appetite suppression and increased satiety resulting in considerable weight loss

• Reduction of liver fat showing promise as a potential therapeutic for Non-Alcoholic Fatty Liver Disease  

Then came Dulaglutide (Trulicity) and Liraglutide (Saxenda, Victoza) in 2014. These longer-acting GLP1 antagonists resulted in larger reductions in HbA1C with fewer gastrointestinal side effects. Improved weight loss outcomes were reported but this was not the primary therapeutic target at the time. 

For our pharmacology nerds, a key difference between the first generation short acting GLP-1 agonists (Exenatide, Lixisenatide) and second generation longer acting formulations (Dulaglutide, Liraglutide) is the base. The former are based on synthetic Exendin-4 whereas the latter are built off Human GLP-1. Pharmacovigilance analysis revealed that -tides based on human analogue-GLP1’s are better tolerated and less likely to cause allergic reactions.

Semaglutide (Ozempic, Wegovy) 

Three years later, a new GLP-1 agonist, Semaglutide, received FDA approval for the management of type-2 diabetes. Semaglutide led to greater reductions in Hba1c and body weight than its predecessors. 

“The primary analysis showed that semaglutide 1.0 mg was significantly more effective than dulaglutide 3.0 mg and comparable with dulaglutide 4.5 mg in reducing HbA1c from baseline. Semaglutide 1.0 mg was also significantly more effective at reducing body weight versus dulaglutide 3.0 and 4.5 mg.” (NCBI) 

It didn’t take long for the news to get out. Semaglutide, brand name Ozempic, made headlines shortly thereafter due to its potent ability to improve metabolic health and support weight-loss efforts. Semaglutide was additionally approved for the reduction of cardiovascular disease risk in diabetics and later for weight loss in non-diabetics in 2021, being rebranded as Wegovy. 

Ongoing investigation has uncovered a multitude of broad-spectrum benefits associated with semaglutide. 

Semaglutide is cardio-protective, reduces neuroinflammation, improves pancreatic beta-cell function, and reverses fatty liver accumulation (hepatic steatosis). The broad-spectrum applications of Semaglutide are evident when we consider that obese individuals often suffer from multiple underlying pathological syndromes such as endothelial dysfunction, hypertension, non-alcoholic fatty liver, neurodegeneration, and dyslipidemia. 

Results from the SELECT cardiovascular outcomes trial made headlines as it was reported that semaglutide used as an adjunct to the current standard of care significantly lowered the incidence of major adverse cardiovascular events (MACE) when compared with placebo. A reduction in MACE of 20% was reported in the 17,604 patients monitored. 

Patients taking Semaglutide in conjunction with proper nutritional oversight, exercise, and lifestyle modification often achieve significant weight loss as a result of reduced appetite and improved insulin sensitivity. There is even potential that it may afford life-long improvement in insulin sensitivity and pancreatic β-cell function, even after treatment has concluded.

Additionally, the areas of the brain associated with reward signaling are densely packed with GLP-1 receptors. Individuals on Semaglutide often report a significant reduction in appetite and disinterest in foods that used to trigger binge eating. Semaglutide is believed to inhibit dopaminergic cascades associated with food and alcohol, affording it with potential utility for clients who struggle with binge eating and substance abuse. 

Therapeutic Frontiers: Tirzepatide

In order to understand the future of GLP1 development, we need to refer back to the past. A number of paragraphs ago, we explored the two primary incretin hormones: GLP-1 and GIP. Both of these hormones influence the metabolic response to food and digestion through overlapping pathways. 

Gastric inhibitory polypeptide(GIP), first extracted from the small intestine of pigs, led to the discovery of the incretin effect. The existence of a second incretin hormone was suggested as complete neutralization of GIP activity reduced but did not totally abolish the incretin effect. 

The continued effort to develop safer and more effective medications for weight loss and metabolic disease has reinvigorated clinical interest in GIP. While the therapeutic potential of GIP-receptor agonists has been acknowledged for some time, clinical integration is a recent development. GIP is the prodigal son finally returning home after a long excursion. 

Tirzepatide (Mounjaro) is a novel dual GLP-1/GIP receptor agonist, approved by the FDA in 2022 for the management of diabetes. The FDA additionally granted expedited status to review Tirzepatide for the management of obesity and weight loss. The combined agonism of both incretin pathways results in clinically significant improvements in patient outcomes.

Therapeutic Frontiers: Tri-Receptor agonists 

Three times the charm? Recently Retatrutide completed Phase II clinical trials. This proposed medication is a tri-receptor agonist, interacting with GIP/GLP1 and the glucagon receptor. Retatrutide is being tested specifically for obesity and weight loss. More research is planned to evaluate the safety and efficacy profile of this medication. 

Exploring Nuanced Approaches to Weight Management

The obesity epidemic puts public health in jeopardy at every strata of society; placing considerable burden on healthcare infrastructure, military readiness, and macroeconomic development, while simultaneously raising direct medical costs on patients and families. Big picture trends aside, it’s nearly impossible not to feel the ramifications of this crisis firsthand. Obesity can take hold of our personal confidence just as much as it dampens our quality of life.

Whether you struggle with excess body fat yourself or care deeply for someone who does, the conclusion is the same… we desperately need an intervention. 

The first step in any successful intervention is fruitful discussion. But in the era of endless content on social media, it can be difficult to differentiate signals from the cacophony of noise. Nuance is a needle in the haystack of one-size-fits-all approaches, quick fixes, fad diets, and over-marketed supplements. 

One of the leading misconceptions arising from the sea of voices is that we only have two paths to address the problem head-on… prevention or intervention. The first camp claims the only solution is to address lifestyle and diet. The other neglects those variables in search of “exercise in a pill.” The notion that there can only be one solution results in a broken record of unfruitful discourse. 

Black-and-white thinking obscures the true colors of any situation. 

Thoughtful prevention is key to safeguarding future generations from the perils of chronic disease. But our 21st-century understanding of genetics, endocrinology, and aging calls into question the assertion that willpower is the only factor at play. 

On the other side of the pendulum, certain weight-loss medications have been remarkably effective for eligible individuals looking to better their health. But these therapies aren’t designed to be shortcuts. In order for them to assist in long-term weight loss, they must be coupled with targeted lifestyle modification and personalized nutrition. 

If you’re interested in nuanced discussion about weight-loss strategies, with or without medication, book an intake consultation with one of our health coaches today. 

Disclaimer: This blog post/article is for informational purposes only and does not constitute medical advice. This is not a substitute for professional medical advice and should not be relied upon. If you are considering a treatment, always consult your primary care physician to discuss the risks and benefits.