GLP1-O (6mg x 90 Capsules = 540mg)
$290.00
GLP1-O: Overview
GLP1-O is a non-peptide GLP-1 receptor agonist. It is like compounds like semaglutide and liraglutide but differs from those peptides in the fact that it is a small non-peptide molecule with excellent oral bioavailability. In trials, GLP1-O has shown weight loss ranging from 8.6% to 12.6% of total body mass over a 26-week period and upwards of 14.7% over 36 weeks. Average weight loss in clinical trials has been on the order of 16 pounds over 40 weeks. Participants showed obvious changes in waist circumference averaging 5.32 cm or roughly two inches [1] .
Besides weight, other metabolic markers of health have been investigated in GLP1-O trials. Trials indicate that this compound reduces total cholesterol, LDL cholesterol and ALT (liver enzyme) levels. Fasting serum glucose (blood sugar) levels are decreased by 23 to 44 mg/gL and hemoglobin A1C levels are reduced as well [2] . As a result of these outcomes, GLP1-O is under direct investigation as a therapeutic for managing diabetes and weight loss.
Of note, GLP1-O is the only orally available GLP-1 receptor agonist other than semaglutide. Whereas semaglutide requires an absorption enhancer (sodium N-(8-[2-hydroxybenzoyl] amino) caprylate) to improve its uptake and must be taken on an empty stomach, GLP1-O does not have these restrictions. It is the first oral GLP-1 agonist being researched with high bioavailability.
GLP1-O: Structure
Source: PubChem
Chemical Formula: C48H48F2N10O5
Molecular Weight: 882.974 g/mol
PubChem CID: 137319706
CAS No.: 2212020-52-3
Synonyms: LY-3502970, OWL833
What Is GLP1-O?
GLP1-O is a small-molecule partial agonist of the GLP-1 receptor. Its activity at the GLP-1 receptor is characterized primarily by cyclic AMP (cAMP) signaling (g-protein coupled receptor activity) and less-so by β-arrestin activity. The cAMP activity is primarily responsible for the induction of glucose metabolism, slowed gastric emptying, and satiety signaling associated with GLP-1 agonists. It is also what promotes beta cell survival and proliferation while inhibiting glucagon release. Thus, cAMP activation is responsible for all the benefits associated with GLP-1 agonists like GLP1-O and semaglutide.
β-arrestin signaling is generally associated with adaptation to persistent stimulus. In the case of therapeutics, this can lead to the phenomenon of tachyphylaxis. In tachyphylaxis, increasing doses of a therapeutic are required to achieve the same effects over time because receptors become desensitized. In extreme cases, this can lead to the need for breaks whereby consumption is stopped for a period to allow the body to “reset.” Because GLP1-O does not have much β-arrestin activity, it is thought that desensitization to the compound will be less likely to occur. This is important because increasing dosages to achieve desired effects generally exacerbates side effects. It is thought that GLP1-O has fewer and less serious side effects than other GLP-1 receptor agonists for precisely this reason.
The oral bioavailability of semaglutide, even when combined with an absorption enhancer, is just 0.4 – 1%. While this will be effective in inducing weight loss, it is important to note that it will NOT be effective in achieving the same weight loss and glucose control seen in trials of SubQ administered semaglutide. Additionally, to achieve that 1% uptake, the oral version of semaglutide needs to be taken on an empty stomach with a proscribed volume of water before consumption of food in the morning. GLP1-O gets around these restrictions due to its unique structure. Research in cynomolgus monkeys shows an oral bioavailability of 21 to 28%. In all other ways, including lowering blood sugar, suppressing appetite, and reducing body weight GLP1-O shows similar outcomes to the currently marketed peptides semaglutide and liraglutide[3]. As a result of its excellent bioavailability and long half-life, GLP1-O can generally be administered orally once per day.
GLP1-O: Research
GLP1-O and Weight Loss Research
Obesity and being overweight are chronic conditions that result from changes to our diet, access to high-density food items, and several unknown factors. Unfortunately, carrying excess weight, which affects more than 1 billion people worldwide, is a major contributor to a premature decline in health. Obesity increases the odds of everything from diabetes and heart disease to cancer and dementia. It should come as no surprise that the medical community has long sought an effective means of inducing weight loss. Several approaches have been tried, but they have turned out to be ineffective or even dangerous. Hope of a pharmacological approach to weight loss was nearly abandoned before the advent of GLP-1 agonists like semaglutide. Now, renewed interest in the GLP-1 receptor is driving innovation in the weight loss industry.
GLP1-O is a GLP-1 agonist, but it differs from the compounds that came before it by not being a peptide. As noted, GLP1-O is a small-molecule partial agonist of the GLP-1 receptor. Its activity, as discussed previously, is biased toward G-protein activation rather than β-arresting recruitment. This makes GLP1-O highly potent and highly selective. Its unique binding pocket on the GLP-1 receptor explains much of this enhanced efficacy profile.
GLP1-O shows highly selective enhanced activity at the GLP-1 receptor due to its unique structure and composition. It is also more likely to reach the GLP-1 receptor due to these same structural features. To date, incretins like semaglutide have had limited oral bioavailability. This is primarily due to enzymatic degradation in the gastrointestinal (GI) tract and the poor permeability of intestinal epithelial cells to intact peptides, both of which are defense mechanisms that serve living organisms well in most situations. Unfortunately, these defense mechanisms reduce oral absorption of most peptide drugs.
GLP1-O is a chemically synthesized, non-peptide oral GLP-1 receptor agonist (GLP-1RA) designed to overcome the limitations of existing GLP-1 agonists. In a 28-day multiple-dose Phase 1 study, once-daily dosing of GLP1-O —administered in both fed and fasted states (fasted when pharmacokinetic or pharmacodynamic sampling was needed)—led to significant weight reduction, comparable to results seen with injected semaglutide in healthy participants. As noted, the average weight loss is 16 pounds over 40 weeks with a reduction in waist circumference of more than 5 cm.
Unlike semaglutide, which has low oral bioavailability (0.4% to 1%) and requires fasting to achieve adequate systemic exposure, GLP1-O demonstrated much higher oral bioavailability (approximately 20%–40%, based on preclinical data)[4]. Food consumption appears to have very little effect on the bioavailability of GLP1-O [5].
GLP1-O in Diabetes Research
GLP-1 receptor agonists are of particular interest in the treatment of diabetes. GLP-1 stimulation can enhance insulin secretion from the pancreas and, more importantly, has been shown to prevent beta-cell apoptosis. Stimulation even increases the formation of new beta cells, thus making GLP-1 receptor stimulation one of the only known mechanisms for reversing diabetes. While most existing diabetes treatments seek only to increase insulin sensitivity or secretion, GLP-1 agonists preserve pancreatic function. This fact makes GLP-1 agonists critical to protecting natural insulin responses and thus normal glucose physiology. This can drastically reduce the long-term effects of diabetes such as cardiovascular disease, kidney disease, and peripheral vascular disease.
Research shows that GLP1-O can reduce A1c values by as much as 2.1% over a 26-week period. This makes GLP1-O significantly more effective than existing diabetes treatments such as metformin and dulaglutide[6], [7]. Compared to placebo, GLP1-O shows decreases in A1c levels and fasting plasma glucose levels while simultaneously showing an increase in fasting plasma insulin levels[8]. As a bonus, GLP1-O appears to have no obvious effect on the odds of severe hypoglycemia. This side effect is often a limiting factor in diabetes treatment. A compound without significant risk of hypoglycemia is considered to have a better safety profile as hypoglycemia can be life-threatening[9].
GLP1-O and Cardiac Research
There are several ways to measure cardiovascular risk. Cholesterol and lipid levels provide excellent screening markers while more advanced studies like CT angiography and cardiac ultrasound are used in the setting of suspected disease to determine treatment. Research has shown that lowering cardiovascular risk factors like high cholesterol, hyperlipidemia, and hyperglycemia can improve long-term outcomes. Doctors have thus long targeted these markers using various medications, lifestyle changes, and sometimes surgery. Incretin peptides, like semaglutide, have shown great benefit not only in lowering blood sugar levels, but in addressing cholesterol and lipid levels as well.
In animal trials of GLP1-O , decreases in total cholesterol, low density lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides were observed at all doses. Each of these reductions is independently associated with an improvement in cardiovascular outcomes but combined they can make a significant difference in risk of future heart attack, stroke, kidney disease, and more.
After 26 weeks of treatment, changes in markers of cardiac health were as follows:
- Total cholesterol: -2.1% to -8.0%
- LDL: -3.7% to -14.3%
- VLDL: -7.1% to -16.4%
- Triglyceride: -8.4% to -16.6%
Additionally, in some test subjects (though not all) HDL levels were increased. HDL is sometimes referred to as “good cholesterol” because high levels of HDL are associated with improved cardiovascular outcomes such as reduced risk of atherosclerosis (hardening of the arteries), heart attack, and stroke.
Research also shows that GLP1-O decreases levels of apolipoprotein B (ApoB) in the blood. ApoB is associated with increased risk of atherosclerosis and increases autoimmune inflammation in the vasculature. It is thought to be the primary driver of plaque formation in the arteries and a major risk factor heart attack, stroke, and kidney disease. In early testing, GLP1-O reduced levels of ApoB by 8.3 to 12.2%, making it one of the most effect treatments against ApoB that has been tested[10].
It is important to note that GLP1-O can improve cardiac outcomes even in non-obese individuals. This is critical because it shows that the compound’s benefits are not strictly linked to weight loss. In a study of normal weight individuals, GLP1-O lowered blood pressure, CRP levels, cholesterol, LDLD, and triglyceride levels significantly enough to alter long-term risk factors for heart attack and stroke[10].
Reviews