Glucagon – like peptide –1 (GLP-1) receptor agonists are incretin analogs that promote glucose mediated insulin release and are used to treat type two diabetes mellitud and obesity.
GLP-1 receptor agonists and GLP-1 and glucose dependent insulinotropic peptide agonists have several mechanisms of action, including reduction of gastric emptying, inhibition of glucagon secretion, beneficial changes in the intestinal microbiome, and direct effects on hypothalamic nuclei to enhance satiety.
GLP-1 is activated by binding to a G protein coupled receptor, which triggers the release of intercellular cyclic AMP and activation of adenyl cyclase:this event drives increase calcium iron uptake through voltage dependent calcium channels with activation of the beta cell.
Injectable and oral agents structurally similar to endogenous GLP-1.
Activate GLP-1 receptors in many issues, that may delay gastric emptying, promote appetite suppression, and typically result in weight loss approximately 2-4 kg.
Only about 27%-53% of patients prescribed GLP –1 agonists were adherent after one year.
Approximately 6 to 10% of patients permanently, discontinue these drugs due to adverse events.
Produce weight loss of 12 to 18%, exceeding any prior pharmacological therapy.
Weight loss plateaus by 12 to 18 months.
Strategies to mitigate common G.I. adverse effects include smaller, planned meals, eating slowly, avoiding fat foods, limiting alcohol and carbonated drinks.
Short term antiemetics are considered for nausea, vomiting, proton pump inhibitors may be initiated for dyspepia and ensuring adequate fiber and hydration may mitigate constipation.
Delayed gastric emptying and decreased thirst, necessitate treatment with bulk laxatives, stool, softeners, or osmotic or stimulant laxatives.
If the drug is stopped the patients generally regain their lost weight within a year.
GLP – 1 agonism has broad effects: redistributes, fat, decrease, inflammation, inhibits, glucagon, production, and delays gastric emptying.
Include exenatide, semaglutide,albiglutide and dulaglutide, tirezpide, and liraglutide.
Stabilize post meal glucagon and help return blood glucose to normal.
GLP –1 receptor agonist have minimal effects on insulin sensitivity in muscle or adipose tissue, but have other indirect effects on glucose tolerance through changes in fat metabolism.
GLP-1 secretion can promote lipid storage reducing circulatory free fatty acids by increasing new lipogenesis and stimulating adipocyte lipoprotein lipase.
These properties enhance the effectiveness of dual therapy to promote glucose tolerance with GLP-1 receptor agonist and GIP receptor agonists.
A1c reduction typically ranges from 0.5% to 2% and can be accompanied by weight loss of typically 2 to 3 kg.
Effects on receptors include increased satiety, decreased gastric emptying, increase glucose uptake by muscle and adipose tissue, decreased glucose production by the liver, and increased insulin secretion.
The effect of GLP-1 on insulin secretion is glucose dependent, and therefore does not lead to hypoglycemia if glucose levels are low.
GLP-1 agonists reduce inflammation, improve insulin signaling, and promote neurogenesis, all of which could protect against cognitive decline.
Once released, GLP-1 is metabolized by dipepidyl peptidase 4 (DPP-4) shortly thereafter.
GLP-1 analogues are ideal message of glycemic controlling combat many of the negative consequences of type two diabetes.
Decrease his hemoglobin A-1 C levels by 0.3%-1.4%, reduce body fat, and induces a small reduction in blood pressure and increase in heart rate.
These agents typically do not cause hypoglycemia, although caution is taken in the setting of multiple glucose lowering therapies.
Gastrointestinal side effects are common.
The most common adverse events are a G.I. issues, including nausea, vomiting, diarrhea, and constipation.
Associated with moderate reduction in substance use and psychotic disorders, poor mental health outcomes, neural cognitive illnesses, like dementia and Alzheimer’s and seizures.
The drug has potential to lower risk of myocardial infarction, heart failure, and stroke.
In patients with cardiometabolic HFpEF, semaglutide and tirzapatide showed more than 40% risk reduction for the composite of hospitalization for heart failure, or all cause mortality compared with placebo.
May be associated with chronic cough.
May help to protect against endometrial cancer, ovarian cancer, and meningioma risk:maybe associated with an increased risk of renal cancer.
May lower the risk of dementia and Alzheimer’s disease.
Gastrointestinal adverse effects are common early after initiation of therapy, affecting 20 to 44% of uses, but these typically subside within the first few months of therapy.
Recent findings found increased risk for pancreatitis, bowel obstruction, gastroparesis biliary disease, gallstones, lung aspiration with anesthesia.
Anesthesia increases risks of gastroparesis.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide (Ozempic) and tirzepatide (Mounjaro) are associated with several health risks.
The most common adverse events are gastrointestinal (GI) in nature, including nausea, vomiting, diarrhea, and abdominal pain.
There is also a risk of pancreatitis and biliary disease.
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported.
Patients with diabetes using glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may face more than twice the risk for developing neovascular age-related macular degeneration compared with those not using the medications,
Renal adverse events, most commonly associated with severe GI losses, may occur.
When used with sulfonylureas or insulin, there is an increased risk of hypoglycemia.
An increased risk of diabetic retinopathy has been noted with semaglutide.
Analysis from cardiovascular outcome trials has shown no increased risk of acute pancreatitis or pancreatic cancer associated with GLP-1 RA treatment.
A pharmacovigilance study using the FDA Adverse Event Reporting System suggested an association between GLP-1 RAs and pancreatic carcinoma, requiring further study.
A Scandinavian study found that use of GLP-1 RAs was associated with a reduced risk of serious renal events compared with dipeptidyl peptidase 4 (DPP-4) inhibitors.
Semaglutide a GLP-1 receptor agonist reduces the risk of clinically important kidney outcomes, and death from cardiovascular causes in patients with type two diabetes and chronic kidney disease.
GLP-1 drugs, mitigate cardiovascular risk in diabetes.
The American College of Cardiology (ACC) has outlined that GLP-1 RAs may increase the risk of gallbladder disease and can lead to elevations in heart rate.
They also note that short-acting GLP-1 RAs may delay gastric emptying, which could impact the absorption of concomitantly administered oral medications.
Some patients cannot tolerate these agents.
They have a higher incidence of pancreatitis and decision should be avoided in patients with history of medullary thyroid cancer or a family history of multiple endocrine neoplasia 2 syndrome due to concern for increase risk of C cell thyroid tumors.
This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.
The treatment of diabetes with GLP-1 receptor agonists is associated with a reduction of more than 50% in the risk of new onset Parkinson’s disease.
In the LEADER study metformin and GLP1RA agents should be added in obese patients because of the potential to promote weight loss.
It is now recommended by the ADA to be the first injectable agent prior to the use of insulin.
In the PIONEER 3 trial Semaglutide, the first oral preparation of a GLP-1RA, resulting in greater glucose lowering and weight loss compared with sitagliptin.
The mechanism of which GLP-1 RAs affect cardiovascular disease are more variable in those with SGLT2 inhibitors.
GLP-1 agonists are injectable agents used a second line therapies to treat type two diabetes.
GLP-1 receptor receptors are widely expressed, particularly in the brain.
GLP-1 increases satiety decreases gastric emptying and has a direct effect on adipocytes as well as cardiovascular tissue and bone.
Daily oral orfoglipon a non-peptide GLP-1 receptor agonist is associated with weight reduction and adverse events similar to injectable GLP-1 receptor agonists.
Weight loss with these agents associated with a 25% weight loss in lean body mass.
With discontinuation of these weight loss agents, patients regain weight primarily as fat.
Cessation of treatment with Semaglutide or Tirezapide results in a regain of 1/2 to 2/3 of the weight loss within one year and the greater relative increase in fat mass than fat free mass in regained weight than in lost weight, suggesting repeated cycles of weight loss and regain will increase whole body adiposity.
Estimates for GLP- 1 RA discontinuation is in the range of 50 to 75% at 12 months.
Studies suggest 2/3 of the weight loss on treatment is regained after this continuation of GLP-1 RA and is associated with worsening cardiometabolic parameters such as glucose levels, blood pressure, and cholesterol levels.
Discontinuation of GLP-1RA may harm patients due to weight cycling, which has been observed in the setting of lifestyle interventions.
Lean muscle mass loss while receiving GLP-1RA therapy may not be regained after discontinuation of the medication, and can produce adverse changes in body composition and increased risk of sarcopenia.
Significant improvement in muscle quality has been noted with the reductions in muscle volume and include reductions in muscle fat infiltration.
Aerobic and resistant exercise are recommended to maintain and improve cardiorespiratory fitness, functional capacity, lean mass and bone health.
People taking GLP1 drugs are much less likely to get vertebral compression fractures, compared with people who were not taking such agents.
The addition of mycostatin inhibitor agents to GLP-1 agonists demonstrated preservation of muscle mass.
GLP-1 receptor agonists are more effective in female patients.
Among patients with moderate to severe obstructive sleep apnea and obesity, tirzepatide reduced the apnea – hypopnea index (AHI)) bodyweight, hypoxic burden, high sensitive CRP concentration and systolic blood pressure and improved sleep related patient reported outcomes.
Among patients with obesity and osteoarthritis of the knee with moderate to severe pain, treatment with semaglutide, resulted in significant reduction in body weight and pain related to knee as arthritis than did placebo.
SGLT2 inhibitors and GLP-1 receptor agonist are associated with lower risk of major adverse cardiac events.: SGLT2 inhibitors are more cardioprotective and older than younger people, despite smaller reductions and hemoglobin A1c and GLP-1 receptor agonist are more cardioprotective in younger people.
GLP-1-receptor agonists have additive effects on both blood glucose levels and body weight loss when combined with GIP agents and glucagon.
In contrast GIP and GLP-1 RAs, glucagon is a counterregulatory hormone that raises blood glucose by stimulating glycogenesis and gluconeogenesis in the liver, and also increases satiety due to its direct effect on the ventral medial hypothalamus: glucagon is in a useful adjunct to incretins because they can reduce intrahepatic fat infiltration, and promote lipolysis.