The long-acting hypoglycemic drug Dulaglutide functions as a glucagon-like peptide-1 (GLP-1) receptor agonist to treat type 2 diabetes mellitus (T2DM). Dulaglutide works through GLP-1 receptor activation by replicating the effects of natural GLP-1 which leads to both insulin secretion promotion and glucagon secretion inhibition while also slowing gastric emptying and reducing blood glucose levels after meals.
Table.1 Dulaglutide related products at Creative Peptides.
Dulaglutide Structure
Dulaglutide represents a synthetic version of human glucagon-like peptide-1 (GLP-1) that consists of two identical peptides joined by disulfide bonds. A modified GLP-1 N-terminal sequence (7-37) together with a modified human immunoglobulin G4 (IgG4) heavy chain (Fc) fragment create a fusion protein that is connected through a small peptide chain in each peptide.
The N-terminal moiety of Dulaglutide resembles human GLP-1 (7-37) but includes critical amino acid changes at positions 8, 22, and 36 to prevent DPP-4 mediated degradation and lengthen its biological half-life to about 90 hours.
The structural features of Dulaglutide include:
Fusion protein form: The fusion protein structure includes two GLP-1-like peptides and the IgG4 Fc fragment which are joined by a small connecting peptide chain.
Amino acid modifications: The N-terminal sequence of Dulaglutide mirrors human GLP-1 (7-37) though specific amino acid substitutions have been made to enhance stability.
Molecular weight: About 63 thousand daltons.
Pharmacokinetic properties: Dulaglutide maintains its activity for roughly 90 hours which enables weekly injections.
The special molecular structure of Dulaglutide produces long-lasting and stable pharmacological traits which make it an effective treatment option for type 2 diabetes.
Dulaglutide Function
Dulaglutide (trade name Trulicity) is primarily used to treat type 2 diabetes. Its main functions are as follows:
Dulaglutide binds to GLP-1 receptors on intestinal and pancreatic islet cells by mimicking the action of endogenous GLP-1, thereby exerting the following physiological effects:
Promotes insulin secretion: When blood sugar levels rise, Dulaglutide stimulates the release of insulin from pancreatic β cells, thereby lowering blood sugar levels.
Inhibition of glucagon secretion: In hyperglycemic states, Dulaglutide reduces glucagon secretion, further stabilizing blood glucose levels.
Slowing down gastric emptying: Dulaglutide slows down the emptying of food in the stomach and increases satiety, thus helping to control dietary intake.
Improves islet β cell function: By increasing the intracellular level of cyclic adenosine monophosphate (cAMP) in pancreatic islet β, it enhances its sensitivity to glucose, thereby improving the ability of insulin synthesis and secretion.
Dulaglutide Mechanism of Action
The mechanism of action of Dulaglutide improves glycemic control in patients with type 2 diabetes mellitus primarily by mimicking the effects of endogenous GLP-1. Here is a detailed description of Dulaglutide's mechanism of action:
Activating the GLP-1 receptor: Dulaglutide promotes insulin secretion by binding to the GLP-1 receptor on pancreatic β cells, activating the intracellular cyclic adenosine monophosphate (cAMP) signaling pathway. This mechanism contributes to the steady release of insulin after a meal and in a fasting state, lowering blood sugar levels.
Inhibition of glucagon: Dulaglutide reduces glucagon secretion and further balances blood sugar levels.
Delayed gastric: Dulaglutide helps control weight by slowing the rate at which the stomach emptying and increasing feelings of fullness, thus reducing food intake.
Reduces hepatic glucose: Dulaglutide further lowers blood sugar levels by inhibiting glucose production in the liver and reducing glucose output from the liver.
Anti-inflammatory and antioxidant: Dulaglutide also has anti-inflammatory and antioxidant effects and is able to reduce inflammatory responses and oxidative stress, which may have a protective effect against diabetes-related complications such as cardiovascular disease and kidney disease.
Long-acting properties: Dulaglutide is a long-acting GLP-1 receptor agonist whose molecular structure contains two disulfide-linked GLP-1 fragments and a human IgG4 hinge region, making it less susceptible to degradation by the DPP-4 enzyme and has a half-life of up to 4.7 days, so it can be administered by once-weekly subcutaneous injection.
Cardiovascular Protective: In the REWIND study, Dulaglutide showed a significant risk reduction effect on cardiovascular events, suggesting that it may protect the cardiovascular system by improving metabolic function and reducing inflammatory response.
Dulaglutide effectively improves blood sugar control in patients with type 2 diabetes by activating GLP-1 receptors, inhibiting glucagon secretion, delaying gastric emptying, decreasing hepatic glucose production, and anti-inflammatory and antioxidant mechanisms, with additional benefits such as weight loss and cardiovascular protection.
Pharmacokinetics and Metabolism
After a subcutaneous administration of dulaglutide at a steady state, the plasma concentration achieves its maximum in 24 to 72 hours. With the subcutaneous injection administrated of 0.75mg and 1.5mg dulaglutide to a steady state, the mean clearance is about 0.111L/h for the 0.75mg dose, and 0.107L/h for the 1.5mg dose, while the volume of distribution is 19.2L (range from 14.3 to 26.4) and 17.4 (range from 9.3 to 33) respectively. Dulaglutide is presumed to be metabolized by general protein catabolism pathways. Its mean elimination half-life is approximately 5 days.
Dulaglutide and Diabetes
Dulaglutide was approved by the U.S. Food and Drug Administration (FDA) on September 18, 2014, for the treatment of type 2 diabetes, based on multiple pieces of evidence. Its mechanism of action includes promoting insulin secretion, delaying gastric emptying, reducing appetite, and improving blood sugar control, while also having some weight loss effects. The following is a detailed summary of the use of Dulaglutide in diabetes:
Blood Sugar Control: Dulaglutide has been shown to significantly reduce HbA1c levels in several studies. For example, in the AWARD-4 trial, the Dulaglutide group experienced a 0.78% to 1.64% reduction in HbA1c from baseline, significantly better than the placebo group (0.53%). In the AWARD-3 trial, HbA1c was reduced by 0.75% to 0.82% in the Dulaglutide arm compared with placebo, and more patients met the target of 7.0% < HbA1c.
Weight management: Dulaglutide has a weight loss effect. In the AWARD-4 trial, patients treated with Dulaglutide lost an average of 1.7 kg of body weight, compared to only 0.6 kg in the placebo group. This weight loss may be related to its effects of delaying gastric emptying and reducing appetite.
Cardiovascular protection: Dulaglutide significantly reduced the risk of major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, or stroke, compared with placebo in the REWIND study.
Table.2 Peptides in diabetes at Creative Peptides.
Other Therapeutic Applications
Dulaglutide and Weight Loss
Dulaglutide is often shown to reduce body weight, but the effects are relatively mild. For example, in one study, after 26 weeks of treatment with a dose of 0.75 mg of Dulaglutide, an average weight loss of 0.62 kg was achieved, while patients with a dose of 1.5 mg lost an average of 2.9 kg. In another study, the average weight loss over 12 months in the Dulaglutide group was 3.2 kg, a result consistent with other observational studies.
Dulaglutide has a significant weight-loss effect in non-diabetic patients, and its mechanism of action includes appetite suppression, delaying gastric emptying, and promoting insulin secretion. However, the weight loss effect is closely related to dose, with higher doses (e.g., 1.5 mg) generally leading to more significant weight loss. In addition, the main side effects of Dulaglutide are gastrointestinal upset, but these side effects are usually mild and resolve over time.
Dulaglutide and Cardiovascular
Dulaglutide has been shown to reduce the risk of cardiovascular events, including the incidence of severe cardiovascular diseases such as myocardial infarction and stroke. For example, in the REWIND study, once-weekly treatment with Dulaglutide significantly reduced the risk of cardiovascular death or non-fatal myocardial infarction. In addition, Dulaglutide has also been used in patients with T2DM who have cardiovascular disease or cardiovascular risk factors to further reduce the risk of cardiovascular events.
Table.3 Cardiovascular disease (CVD) related peptides at Creative Peptides.
Dulaglutide and Kidneys
Dulaglutide has a protective effect on kidney function, can improve renal function indicators in patients with chronic kidney disease, and reduce the risk of end-stage renal disease (ESRD). In the REWIND study, Dulaglutide also showed beneficial long-term effects in patients with chronic kidney disease.
Summary
Dulaglutide not only effectively controls blood sugar levels in patients with type 2 diabetes, but also has multiple benefits of weight reduction and protection of cardiovascular and kidney function. Its long-term properties allow patients to receive weekly injections, improving the convenience of treatment. By further studying Dulaglutide, we can further understand the potential of GLP-1 receptor agonists in a variety of metabolic diseases, and provide new therapeutic strategies for the future treatment of diabetes and its complications.
FAQs
1. Is dulaglutide the same as Ozempic?
No, dulaglutide and Ozempic are different drugs. Dulaglutide is branded as Trulicity, while Ozempic contains semaglutide. Both are GLP-1 receptor agonists for type 2 diabetes.
2. Is dulaglutide the same as Trulicity?
Yes, dulaglutide is the active ingredient in Trulicity. It is a GLP-1 receptor agonist used for managing blood glucose levels and reducing cardiovascular risks in type 2 diabetes patients.
3. Is dulaglutide approved for weight loss?
Dulaglutide is not officially approved for weight loss but may cause weight reduction as a secondary benefit during type 2 diabetes treatment.
4. What class of drug is dulaglutide?
Dulaglutide belongs to the GLP-1 receptor agonist class, which mimics incretin hormones to enhance insulin secretion, suppress glucagon, and slow gastric emptying.
References
- Nadkarni, Prashant, et al., Regulation of glucose homeostasis by GLP-1. Progress in molecular biology and translational science 121 (2014): 23-65.
- Sanford, Mark. Dulaglutide: first global approval. Drugs 74 (2014): 2097-2103.
- Tibble, Courtney Aavang, et al., Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature. Expert Review of Endocrinology & Metabolism 8.3 (2013): 247-259.
