GLP-1's in a Pill vs. a Jab

Most people prefer to take medicine in a pill format versus an injection. Is it a big enough preference that patients will prefer a less effective pill vs. a more effective injection?

Two thirds of U.S. adults take prescription drugs, and the vast majority of those are in pill format.¹ It hasn’t been until this GLP-1 revolution that subcutaneous injections have become a relatively common administration of medicine. Drugmakers are working on pill based versions of existing GLP-1’s and in new small molecule versions. I’ll attempt to explain how these work and why pills vs. injections.

Peptides

Peptide drugs are typically injected subcutaneously, which is relatively shallow below the skin. A peptide is a linkage of amino acids (organic chemicals) that create a structure that can fit into cell surface receptors. These receptors then signal to the body to perform some function. Pharmaceutical peptides, like GLP-1 agonists, tend to be complex structures that are very similar in structure to the hormones made by our own bodies.

Amino acids are the building blocks of protein, which our digestive tract quickly breaks down. The structure of the molecule is also typically too large to easily permeate the gut / blood stream barrier. Most GLP-1 drugs are between 29-42 amino acid linkages. The average amino acid has a molecular size of 110 Daltons, so the size of GLP-1 drugs is between 3190 - 4620 Daltons. Molecules of less than 600 Daltons efficiently pass through the gut / blood barrier,² so peptides tend to be too large to efficiently find their way into our blood stream. Due to these factors, administration of peptides in pill form doesn’t work very well. There are a number of inventions that show promise in circumventing these challenges (and a good future article for me to write!).

Small Molecules

Nearly all oral drugs are small molecules. These are non-organic chemical structures that are quite a bit less complex than peptide structures, can be effective in interacting with cell surface receptors. Small molecules are being developed to perform similar functions to peptide based GLP-1 agonists. The inorganic structure isn’t degraded by our digestive system. The small size (between 500-599 Dalton, 4-9x smaller than GLP-1 peptides) allows it to pass through the gut / blood barrier and enter our blood stream.

Advantages of Peptides

The complex structure of a peptide can be designed to interact with multiple receptors. For example, Mounjaro / Zepbound / Tirzepatide (all the same peptide) interact with both GLP-1 receptors and GIP receptors. The structure of Tirzepatide causes the molecule to interact with GIP at a rate of five times higher than it does with GLP-1 as the structure is molecularly very similar to GIP, and less similar to GLP-1.³ The functionality of a peptide is greatly enhanced over a small molecule due to this flexibility.

Our bodies are very effective at removing foreign materials, so native peptides (peptides produced in our bodies, typically our pancreas) have a short life span to perform their function. Advances in peptides allow a much longer half life, both by being able to sit in a deposit under the skin and be slowly released, and more importantly to be able to bind to albumin in the blood stream and avoid being removed by the liver. Current GLP-1’s are typically weekly administration vs. the daily administrations of previous generation GLP-1’s.

Advantages of Small Molecules

The big one is taking a pill instead of an injection— most folks don’t like the idea of having to take a weekly injection. The small molecule GLP-1’s under development are taken daily.

Making a small molecule drug is an easier process than a peptide. It is linking fewer chemicals together in a streamlined process that already exists to make other drugs on a mass scale. Peptide production is a more complicated process, and the facilities to make the peptides and package them are in short supply. It is conceivable that small molecule GLP-1’s could be considerably less expensive than peptide GLP-1’s.

A peptide that is diluted into liquid has a limited shelf life and needs to be stored in a refrigerated environment at a relatively constant temperature. A small molecule can tolerate a large range of temperatures and has a much longer shelf life. These qualities make them much easier & less expensive for the supply chain and much simpler for the patient.

The Known Unknowns

The focus on GLP-1’s as a weight loss tool is clearly understood as very powerful & effective at quickly reducing body weight. We also know that in order to maintain a certain weight, these are long term / forever drugs, like blood pressure medication or statins tend to be. However, the long term impact of this class of drugs is not known because they haven’t been in existence for very long.

We are starting to understand that currently available GLP-1 drugs cause both a loss of fat mass and lean mass, such as muscle and bone. Weight loss through diet and exercise also cause a loss of fat and lean mass, typically a ratio of 25% lean mass to 75% fat mass.⁴ This makes sense because when our bodies have excess fat, there is an associated muscle & bone infrastructure needed to support the weight. Most GLP-1 drugs have shown a higher lean mass loss than diet and exercise alone. A single agonist GLP-1 has shown up to 40% lean mass loss in a 72 week clinical trial.⁵ The body requires more energy when there is a greater amount of lean mass compared to fat mass, so a reduction in lean mass will reduce metabolic rate. A reduced metabolic rate means the body requires fewer calories to maintain equilibrium weight. Those who discontinue the drug will be in a position to have less muscle while fat is relatively rapidly regained, likely in a worse physical condition than if they hadn’t taken the GLP-1 drugs in the first place. It is not known how lean mass is impacted over a longer term than 72 weeks.

We also do not know how small molecule GLP-1 agonists will impact lean mass loss. We do know that GLP-1’s cause people to consume less calories, which leads the body to use energy stored within the body, such as fat and protein. An agonist that only interacts with the GLP-1 receptor seems to be more likely to cause a greater proportion of lean mass loss than those with multiple agonists. Ozempic / Wegovy (Semaglutide) only interacts with GLP-1 receptors and has the 40% lean mass loss at 72 weeks as previously mentioned. Multi-agonists such as Tirzepatide (GIP & GLP-1) and Pemvidutide (GLP-1 and GCGR) appear to be able to maintain lean mass at a higher rate. Tirzepatide has a lean mass loss of approximately 29%,⁶ where Pemvidutide has an industry leading lean mass loss of approximately 21%.⁷

Which Is Better?

My prediction is peptide-based GLP-1’s and similar agonists will in the long term be the gold standard for this class of medicine in terms of body composition. The elderly, health nuts, and those with health conditions where loss of lean mass puts them at a higher risk. Small molecules have the potential to bring this class of medication to a wider demographic, and additional small molecules may be able to address some of the downsides of single agonist weight loss medications. Both are needed to address the obesity epidemic.

Disclaimer: This article is intended for informational purposes only and does not constitute medical or financial advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment. While I strive to be factual at all times, I cannot guarantee the accuracy of these statements.

1. https://www.singlecare.com/blog/news/prescription-drug-statistics/

2. https://pmc.ncbi.nlm.nih.gov/articles/PMC6104804/

3. https://pmc.ncbi.nlm.nih.gov/articles/PMC7526454/

4. https://pmc.ncbi.nlm.nih.gov/articles/PMC3970209/

5. https://pubmed.ncbi.nlm.nih.gov/38629387/

6. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

7. https://www.hcplive.com/view/momentum-pemvidutide-boasts-class-leading-lean-mass-preservation-with-weight-loss