Metformin is not an incretin hormone or incretin mimetic—it belongs to a different class of diabetes medicines called biguanides. This distinction is important for understanding how metformin works and how it differs from incretin-based therapies such as GLP-1 receptor agonists. Whilst metformin may have some indirect effects on incretin pathways, its primary glucose-lowering actions occur through entirely different mechanisms, principally by reducing hepatic glucose production and improving insulin sensitivity. This article clarifies the relationship between metformin and incretins, explains how each works, and outlines the key differences between these treatment approaches for type 2 diabetes.

What Are Incretins and How Do They Work?

Incretins are naturally occurring hormones produced in the gastrointestinal tract that play a crucial role in regulating blood glucose levels after eating. The two primary incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both secreted by specialised cells in the small intestine in response to food intake.

These hormones work through what is known as the incretin effect, which accounts for a substantial proportion of insulin secretion following oral glucose intake. When food enters the digestive system, incretin hormones are released into the bloodstream and travel to the pancreas, where they stimulate insulin secretion from beta cells in a glucose-dependent manner. This means they only promote insulin release when blood glucose levels are elevated, thereby reducing the risk of hypoglycaemia.

The two incretin hormones have distinct effects. GLP-1 has several important metabolic actions:

• Stimulation of insulin secretion in a glucose-dependent manner

• Suppression of glucagon secretion from pancreatic alpha cells, which reduces hepatic glucose production

• Slowing of gastric emptying, which moderates the rate at which glucose enters the bloodstream

• Promotion of satiety, which may help with weight management

GIP also stimulates glucose-dependent insulin secretion, but its other effects differ from GLP-1. In people with type 2 diabetes, beta-cell responsiveness to GIP is markedly reduced.

In people with type 2 diabetes, the incretin effect is significantly diminished, contributing to inadequate insulin secretion and poor glycaemic control. This impairment occurs primarily due to reduced GLP-1 secretion from the gut and impaired pancreatic beta-cell responsiveness to both incretin hormones. Understanding this mechanism has led to the development of incretin-based therapies, which aim to restore or enhance incretin activity to improve diabetes management.

Is Metformin an Incretin or Incretin Mimetic?

Metformin is neither an incretin hormone nor an incretin mimetic. This is an important distinction that often causes confusion among patients and even some healthcare professionals. Metformin belongs to a completely different class of diabetes medicines called biguanides and works through entirely different mechanisms from incretin-based therapies.

Incretin mimetics, also known as GLP-1 receptor agonists, are synthetic compounds that mimic the action of natural GLP-1 hormone. Examples include semaglutide, liraglutide, and dulaglutide. These medicines are available as subcutaneous injections (daily or weekly, depending on the specific agent) or, in the case of semaglutide, as an oral tablet (Rybelsus). GLP-1 receptor agonists bind to and activate GLP-1 receptors, producing effects similar to natural incretin hormones. Metformin does not interact with incretin receptors and does not replicate incretin hormone activity.

However, emerging research suggests that metformin may have some indirect effects on incretin pathways. Some studies have shown that metformin treatment can lead to modest increases in circulating GLP-1 levels, though the clinical significance of this effect remains uncertain and requires further investigation. Proposed mechanisms include alterations in gut microbiota composition, changes in bile acid metabolism, and possible direct effects on intestinal L-cells that produce GLP-1.

Despite these potential indirect effects, it would be inaccurate to classify metformin as an incretin-based therapy. The drug's primary glucose-lowering actions occur through completely different pathways, and any incretin-related effects are considered secondary and relatively minor compared to its main mechanisms of action. When prescribing diabetes medicines, clinicians categorise metformin separately from incretin therapies in treatment algorithms recommended by NICE and other guideline bodies.

Differences Between Metformin and Incretin-Based Therapies

Metformin and incretin-based therapies differ substantially in their mechanisms of action, administration routes, side effect profiles, and clinical applications. Understanding these differences helps patients and healthcare professionals make informed treatment decisions.

Mechanism and glucose-lowering effects: Metformin primarily reduces hepatic glucose production and improves insulin sensitivity in peripheral tissues, whilst incretin therapies enhance glucose-dependent insulin secretion and suppress glucagon. Metformin does not directly stimulate insulin release, making hypoglycaemia extremely rare when used alone. Incretin-based drugs work in a glucose-dependent manner, also conferring low hypoglycaemia risk when used as monotherapy. However, when metformin is combined with insulin or sulfonylureas, the risk of hypoglycaemia increases.

Administration and formulation: Metformin is taken orally, typically as tablets or modified-release preparations, making it convenient for most patients. GLP-1 receptor agonists are available as subcutaneous injections (daily or weekly, depending on the agent) or as an oral tablet (semaglutide/Rybelsus). DPP-4 inhibitors are oral tablets. This difference in administration can significantly influence patient preference and adherence.

Weight effects: Metformin is generally weight-neutral or may produce modest weight loss. GLP-1 receptor agonists typically cause more substantial weight reduction, making them particularly valuable for patients with type 2 diabetes and obesity, though the degree of weight loss varies by agent and dose. DPP-4 inhibitors are weight-neutral.

Gastrointestinal side effects: Both metformin and GLP-1 agonists commonly cause gastrointestinal symptoms, though the nature differs. Metformin frequently causes diarrhoea, abdominal discomfort, and metallic taste, particularly when initiating therapy. GLP-1 agonists more commonly cause nausea, vomiting, and reduced appetite. These effects usually diminish over time with both drug classes.

Cardiovascular and renal benefits: Cardiovascular outcome trials have demonstrated that certain GLP-1 receptor agonists reduce major adverse cardiovascular events in high-risk patients. Metformin has long been considered to have cardiovascular benefits. SGLT2 inhibitors have established benefits in reducing heart failure hospitalisations and slowing progression of chronic kidney disease. NICE guidelines now recommend considering these cardiovascular and renal protective effects when selecting second-line therapies for type 2 diabetes.

How Metformin Works to Lower Blood Sugar

Metformin exerts its glucose-lowering effects through multiple complementary mechanisms, with the primary action occurring in the liver. Understanding these mechanisms helps explain why metformin remains the first-line pharmacological treatment for type 2 diabetes, as recommended by NICE guidelines.

Reduction of hepatic glucose production: The most significant effect of metformin is suppression of gluconeogenesis—the process by which the liver produces new glucose from non-carbohydrate sources. In type 2 diabetes, excessive hepatic glucose output, particularly during fasting, contributes substantially to hyperglycaemia. Metformin reduces glucose release into the bloodstream through effects on liver metabolism.

Improved insulin sensitivity: Metformin enhances insulin action in peripheral tissues, particularly skeletal muscle. This improved insulin sensitivity allows cells to take up glucose more efficiently from the bloodstream in response to insulin.

Effects on the gastrointestinal tract: Metformin increases glucose uptake in the intestinal wall, reducing the amount of glucose absorbed into the circulation. It also appears to alter the gut microbiome composition, which may contribute to its metabolic benefits through mechanisms that are still being investigated.

Additional metabolic effects: Beyond glucose control, metformin favourably affects lipid metabolism, modestly reducing triglycerides and LDL cholesterol. It does not stimulate insulin secretion, which explains why hypoglycaemia is exceptionally rare with metformin monotherapy.

Dosing and administration: The typical starting dose is 500 mg once daily with or after food, gradually titrated at weekly intervals to minimise gastrointestinal side effects. The usual maintenance dose is 1.5–2 g daily in divided doses. The maximum dose is 3 g daily for immediate-release tablets or 2 g daily for modified-release preparations. Modified-release formulations may improve tolerability for some patients.

Important safety information: Metformin is contraindicated in severe renal impairment (eGFR below 30 mL/min/1.73 m²). If your eGFR is between 30 and 44 mL/min/1.73 m², your doctor will review your dose and may reduce it. Renal function should be monitored at least annually, or more frequently if you are at increased risk of deterioration. Metformin should be temporarily discontinued during acute illness that may affect kidney function (such as severe dehydration, serious infection, or shock) and before certain procedures requiring iodinated contrast media. If you have an eGFR between 30 and 60 mL/min/1.73 m² and are undergoing intra-arterial contrast administration or a large intravenous contrast load, metformin should be stopped beforehand; your kidney function will be rechecked at least 48 hours after the procedure before restarting metformin.

Vitamin B12 deficiency: Long-term use of metformin may reduce vitamin B12 levels. The MHRA advises that if you develop symptoms such as extreme tiredness, sore red tongue, pins and needles, or pale or yellow skin, you should contact your GP, as these may indicate vitamin B12 deficiency. Your doctor may consider periodic monitoring of vitamin B12 levels, particularly if you are at higher risk.

Lactic acidosis: Although very rare, lactic acidosis is a serious side effect. Seek urgent medical attention if you experience symptoms such as feeling very weak or tired, unusual muscle pain, difficulty breathing, stomach pain with nausea or vomiting, or feeling unusually cold.

If you experience persistent gastrointestinal symptoms or inadequate blood glucose control, contact your GP or diabetes care team for a medication review. You can report suspected side effects via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk.

Frequently Asked Questions