Trulicity (dulaglutide) is a once-weekly injectable medication used to improve blood glucose control in adults with type 2 diabetes mellitus. Understanding Trulicity's mechanism of action helps explain how this glucagon-like peptide-1 (GLP-1) receptor agonist works to lower blood sugar levels whilst minimising the risk of hypoglycaemia. By mimicking a naturally occurring hormone, Trulicity enhances insulin secretion when glucose is elevated, suppresses glucagon release, and slows gastric emptying. This article explores the detailed pharmacological mechanisms, clinical effects, and metabolic benefits of Trulicity in diabetes management, providing essential information for patients and healthcare professionals.

What Is Trulicity and How Does It Work?

Trulicity (dulaglutide) is a prescription medicine used to improve blood sugar control in adults with type 2 diabetes mellitus. It belongs to a class of medications called glucagon-like peptide-1 (GLP-1) receptor agonists, which work by mimicking the action of a naturally occurring hormone in the body. Trulicity is administered as a once-weekly subcutaneous injection, typically in the abdomen, thigh, or upper arm, using a pre-filled, single-dose pen device.

The medication is licensed in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA). NICE guidance (NG28) recommends GLP-1 receptor agonists like Trulicity in specific circumstances, typically when other treatments haven't achieved adequate blood glucose control and when certain other criteria are met. Treatment usually starts at 0.75 mg once weekly, which may be increased to 1.5 mg after at least 4 weeks. If needed, doses can be further increased to 3.0 mg and then 4.5 mg at intervals of at least 4 weeks.

Trulicity works by enhancing the body's natural insulin response when blood glucose levels are elevated, whilst also reducing the release of glucagon, a hormone that raises blood sugar. Additionally, it slows gastric emptying, which helps to moderate post-meal glucose spikes. Trulicity has been associated with modest weight loss in many patients, which can be beneficial for individuals with type 2 diabetes who are also overweight or obese.

It is important to note that Trulicity is not suitable for treating type 1 diabetes or diabetic ketoacidosis. It is not recommended during pregnancy or breastfeeding, and should be used with caution in people with severe gastrointestinal disease, including gastroparesis. Patients should always use this medication under the guidance of their healthcare professional, who will tailor treatment to individual clinical needs and monitor for potential side effects.

Trulicity's Mechanism of Action: GLP-1 Receptor Activation

The therapeutic action of Trulicity centres on its ability to activate GLP-1 receptors, which are found in various tissues throughout the body, including the pancreas, gastrointestinal tract, and brain. Dulaglutide is a long-acting GLP-1 receptor agonist that has been structurally modified to resist degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), which normally breaks down natural GLP-1 within minutes. This modification allows Trulicity to remain active in the body for approximately one week, enabling convenient once-weekly dosing.

When Trulicity binds to GLP-1 receptors on pancreatic beta cells, it stimulates glucose-dependent insulin secretion. This means that insulin is released only when blood glucose levels are elevated. When used alone, this significantly reduces the risk of hypoglycaemia (dangerously low blood sugar) compared to some other diabetes medications such as sulphonylureas or insulin. However, when used in combination with these medications, the risk of hypoglycaemia may increase. This glucose-dependent mechanism is a key safety feature of GLP-1 receptor agonists.

Simultaneously, Trulicity suppresses the secretion of glucagon from pancreatic alpha cells. Glucagon is a hormone that signals the liver to release stored glucose into the bloodstream. In people with type 2 diabetes, glucagon levels are often inappropriately elevated, contributing to hyperglycaemia. By reducing glucagon secretion in a glucose-dependent manner, Trulicity helps to prevent excessive hepatic glucose output, particularly during fasting states.

The pharmacological profile of dulaglutide also includes effects on gastric motility and appetite regulation, which are mediated through GLP-1 receptors in the gastrointestinal tract and central nervous system. It's worth noting that with long-acting GLP-1 receptor agonists like Trulicity, the effect on gastric emptying may diminish somewhat over time with continued use. These additional actions contribute to the medication's broader metabolic benefits beyond glucose control alone.

Clinical Effects: What Happens in Your Body

Once administered, Trulicity exerts several coordinated effects that work together to improve metabolic control in people with type 2 diabetes. One of the most clinically significant actions is the slowing of gastric emptying. By delaying the rate at which food leaves the stomach and enters the small intestine, Trulicity helps to moderate the post-meal rise in blood glucose levels. This effect can also contribute to increased feelings of fullness (satiety), which may reduce overall calorie intake.

In the pancreas, Trulicity's activation of GLP-1 receptors leads to enhanced insulin biosynthesis and secretion when blood glucose is elevated. This glucose-dependent insulin release helps to lower blood sugar levels effectively whilst minimising the risk of hypoglycaemia. Clinical trials have demonstrated that Trulicity can reduce HbA1c (a measure of average blood glucose over the preceding two to three months) by approximately 0.8% to 1.5% with the 0.75 mg and 1.5 mg doses, with potentially greater reductions at the higher 3.0 mg and 4.5 mg doses.

Beyond glycaemic effects, Trulicity has been associated with modest weight reduction in many patients, typically in the range of 2 to 3 kilograms over several months, with potentially greater weight loss at higher doses. This weight loss is thought to result from a combination of delayed gastric emptying, reduced appetite, and decreased caloric intake. For individuals with type 2 diabetes who are overweight, this additional benefit can be clinically meaningful.

Cardiovascular effects have also been observed in clinical trials. The REWIND study demonstrated that Trulicity reduced the risk of major adverse cardiovascular events (including heart attack, stroke, and cardiovascular death) in people with type 2 diabetes, many of whom had established cardiovascular disease or multiple cardiovascular risk factors. This evidence is important for clinical decision-making, though it's worth noting that Trulicity is not specifically licensed for cardiovascular risk reduction in the UK.

How Trulicity Affects Blood Sugar and Weight

Trulicity's impact on blood glucose control is multifaceted and operates through several complementary mechanisms. The medication enhances insulin secretion in response to meals, suppresses inappropriate glucagon release, and slows the absorption of nutrients from the gastrointestinal tract. Together, these actions help to reduce both fasting and post-meal blood glucose levels, leading to improved overall glycaemic control as reflected in HbA1c measurements.

The glucose-lowering effect is most pronounced when blood sugar levels are elevated, which is an important safety feature. As blood glucose approaches normal levels, the insulin-stimulating effect of Trulicity diminishes, thereby reducing the risk of hypoglycaemia when used alone. However, when Trulicity is used in combination with other glucose-lowering medications—particularly sulphonylureas or insulin—the risk of hypoglycaemia may increase, and dose reductions of these concomitant medications may be necessary.

Regarding weight management, Trulicity's effects are primarily mediated through appetite suppression and delayed gastric emptying. Patients often report feeling fuller for longer after meals, which can lead to reduced food intake and gradual weight loss. It is important to note that weight loss varies considerably between individuals, and not all patients will experience significant weight reduction. Lifestyle modifications, including a balanced diet and regular physical activity, remain essential components of diabetes management and can enhance the weight-related benefits of Trulicity.

Common side effects of Trulicity include nausea, vomiting, diarrhoea, and abdominal discomfort, particularly when starting treatment. These gastrointestinal symptoms are generally mild to moderate and tend to improve over time. Patients should maintain adequate hydration, especially if experiencing gastrointestinal side effects, to reduce the risk of dehydration and potential kidney problems. They should contact their GP or diabetes specialist if they experience persistent or severe symptoms, signs of pancreatitis (severe abdominal pain radiating to the back), or symptoms of gallbladder disease (pain in the right or middle upper abdomen). Rare but serious hypersensitivity reactions can occur. The MHRA SmPC notes that rodent studies showed C-cell thyroid tumours, though the relevance to humans is unknown. Suspected side effects can be reported through the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk). Regular monitoring and follow-up are essential to ensure safe and effective use of this medication.

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