H-His-Gly-Glu-Gly-aThr-Phe-aThr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-D-Ala-D-Ala-Lys-Glu-Phe-aIle-D-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH2

Q1: What is the mechanism of action of albiglutide?

A1: Albiglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). [] It exerts its therapeutic effect by binding to and activating GLP-1 receptors. [, , ] This activation triggers a cascade of downstream effects, primarily in the pancreas:

• Increased Insulin Secretion: Albiglutide enhances glucose-dependent insulin secretion from pancreatic β-cells. [, , ] This means insulin release is amplified when blood glucose levels are elevated, such as after a meal.
• Decreased Glucagon Secretion: Simultaneously, albiglutide suppresses glucagon secretion from pancreatic α-cells. [, , ] Glucagon normally raises blood glucose levels; therefore, its suppression contributes to improved glycemic control.

Q2: What are the additional effects of albiglutide beyond the pancreas?

A2: In addition to its pancreatic effects, albiglutide influences other physiological processes:

• Delayed Gastric Emptying: Albiglutide slows down the rate at which food empties from the stomach into the small intestine. [, , ] This contributes to a feeling of fullness and can help regulate post-meal blood glucose levels.
• Increased Satiety: Albiglutide acts on the central nervous system to promote a sense of satiety or fullness, further contributing to its potential for weight management. [, , ]

Q3: What is the molecular structure of albiglutide?

A4: Albiglutide is a large molecule comprised of two identical chains of modified human glucagon-like peptide-1 (GLP-1) linked to a recombinant human albumin molecule. [, , ] The specific modifications within the GLP-1 chains confer resistance to DPP-4 degradation, a key factor in its extended half-life.

Q4: What are the molecular formula and weight of albiglutide?

A4: Due to the complexity of albiglutide's structure as a fusion protein, providing a precise molecular formula and weight is not straightforward. It's more relevant to consider its amino acid sequence and modifications when understanding its properties.

Q5: Is there spectroscopic data available for albiglutide?

A5: Spectroscopic data, such as that from nuclear magnetic resonance (NMR) or mass spectrometry, is crucial for characterizing protein structure. While publicly available research articles may not always provide this detailed data, it's likely utilized during the drug development process to confirm albiglutide's identity, purity, and structural integrity.

Q6: How is albiglutide absorbed and distributed in the body?

A7: Following subcutaneous administration, albiglutide is primarily absorbed via the lymphatic circulation. [] Its distribution is largely influenced by its fusion to human albumin, a protein abundant in plasma. This fusion contributes to its long half-life and allows for once-weekly dosing. [, , ]

Q7: How is albiglutide metabolized and excreted?

A8: As a large peptide, albiglutide's metabolism differs from small molecule drugs. It's likely broken down into smaller peptides and amino acids through proteolysis, a process involving enzymes. While specific details on its metabolic pathways may not be extensively published, its elimination half-life of approximately 5 days suggests a slow clearance process. [, ]

Q8: How does albiglutide affect glucose levels in patients with type 2 diabetes?

A9: Clinical trials consistently demonstrate albiglutide's efficacy in lowering both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), with HbA1c reductions ranging from -0.55% to -0.9%. [, , , , , , , , ] This glucose-lowering effect is attributed to its multi-faceted mechanism involving increased insulin secretion, decreased glucagon secretion, and delayed gastric emptying. [, , , ]

Q9: Does albiglutide cause weight loss?

A10: While albiglutide doesn't typically cause significant weight loss compared to placebo, clinical trials have shown it can lead to modest weight reductions ranging from +0.28 to -1.21 kg, depending on the comparator drug and study population. [, , , , , , , , ] Its weight management potential is attributed to its ability to increase satiety and slow gastric emptying. [, , ]

Q10: Has albiglutide been tested in preclinical models?

A11: Yes, preclinical studies in rats have demonstrated albiglutide's protective effects against ischemia/reperfusion injury, a condition that deprives the heart of oxygen. [] The study found that albiglutide significantly reduced infarct size and improved cardiac function and energetics post-injury. [] These benefits were associated with enhanced myocardial glucose uptake and a shift towards a more favorable cardiac metabolism. []

Q11: What were the main findings of the HARMONY clinical trial program?

A12: The HARMONY program encompassed eight Phase III clinical trials, representing a comprehensive evaluation of albiglutide's efficacy and safety in various patient populations with type 2 diabetes. [, , , , , , , ] These trials compared albiglutide to placebo, other GLP-1 receptor agonists, and other classes of diabetes medications, revealing key findings:

• Superior Glycemic Control: Albiglutide consistently demonstrated superior reductions in HbA1c and fasting plasma glucose compared to placebo and certain active comparators, including sitagliptin and glimepiride. [, , , , , , , ]
• Weight Management: While not as potent as some other GLP-1RAs in this regard, albiglutide demonstrated either weight neutrality or modest weight loss in some trials. [, , , , , , , ]
• Cardiovascular Safety: A key concern with diabetes medications is their potential impact on cardiovascular health. The HARMONY Outcomes trial, a major component of the program, investigated albiglutide's cardiovascular safety in patients with established cardiovascular disease. [] Notably, it demonstrated a 25% relative risk reduction in myocardial infarction (heart attack) across various infarction types. []

Q12: What is the safety profile of albiglutide?

A13: In clinical trials, albiglutide demonstrated a generally favorable safety and tolerability profile. [, , , , , , , , ] The most common adverse events were gastrointestinal in nature, primarily:

• Nausea: Experienced by a greater proportion of patients receiving albiglutide compared to placebo, but generally mild to moderate in severity. [, , ]
• Diarrhea: Similar in incidence to nausea, typically mild to moderate, and often resolving with continued treatment. [, , ]
• Injection Site Reactions: Reported in a smaller percentage of patients, typically characterized by redness or mild pain at the injection site. [, , ]

Q13: Are there any serious safety concerns associated with albiglutide?

A14: While albiglutide is generally well-tolerated, there have been rare reports of pancreatitis (inflammation of the pancreas) associated with its use. [, , ] Patients with a history of pancreatitis should avoid albiglutide. [, , ] Additionally, as with other GLP-1RAs, a potential risk for thyroid C-cell tumors has been observed in rodent studies, though it remains unclear whether this translates to humans. [] Albiglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2. []