Incretin mimetics and DPP-4 inhibitors are two important classes of glucose-lowering medications used to manage type 2 diabetes in the UK. Both work by enhancing the body's natural incretin system—a hormonal pathway that regulates blood sugar in response to food—but they do so through different mechanisms. Incretin mimetics (GLP-1 receptor agonists) directly mimic the action of the hormone GLP-1, whilst DPP-4 inhibitors (gliptins) prolong the activity of the body's own incretin hormones. Understanding the differences between these treatments helps patients and clinicians make informed decisions about diabetes management, particularly when first-line therapies such as metformin prove insufficient.

What Are Incretin Mimetics and DPP-4 Inhibitors?

Incretin mimetics and DPP-4 inhibitors represent two distinct classes of glucose-lowering medications used primarily in the management of type 2 diabetes mellitus. Both drug classes work by enhancing the incretin system, a natural hormonal pathway that regulates blood glucose levels in response to food intake. These medications have become increasingly important therapeutic options since their introduction in the mid-2000s, offering alternatives to traditional diabetes treatments such as metformin, sulphonylureas, and insulin.

Incretin mimetics, also known as GLP-1 receptor agonists, are medications that mimic the action of glucagon-like peptide-1 (GLP-1), a naturally occurring incretin hormone. Most are administered by subcutaneous injection, though an oral formulation (semaglutide, Rybelsus) is also available in the UK. Common examples include exenatide (Bydureon BCise), liraglutide (Victoza), dulaglutide (Trulicity), and semaglutide (Ozempic for injection, Rybelsus for oral use). These agents directly stimulate GLP-1 receptors throughout the body, producing effects that extend beyond glucose control.

DPP-4 inhibitors, also called gliptins, are oral medications that work by blocking the enzyme dipeptidyl peptidase-4, which normally breaks down incretin hormones. By inhibiting this enzyme, these drugs prolong the activity of the body's own GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Examples include sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Onglyza), linagliptin (Trajenta), and alogliptin (Vipidia).

Important: Do not use a GLP-1 receptor agonist together with a DPP-4 inhibitor, as combining them provides no additional benefit.

Both medication classes are recommended by NICE for use in type 2 diabetes when first-line treatments prove insufficient, though they differ significantly in their administration routes, potency, and additional clinical benefits. SGLT2 inhibitors represent another important option for treatment intensification in current UK pathways. Understanding these differences helps clinicians and patients make informed treatment decisions tailored to individual circumstances and therapeutic goals.

How These Medications Work to Control Blood Sugar

The incretin system plays a crucial role in maintaining glucose homeostasis, and both incretin mimetics and DPP-4 inhibitors harness this physiological pathway through different mechanisms. Understanding their pharmacology helps explain their therapeutic effects and clinical applications.

Incretin mimetics function as synthetic analogues of GLP-1, binding directly to and activating GLP-1 receptors on pancreatic beta cells. This activation triggers several glucose-lowering mechanisms:

• Enhanced insulin secretion: These agents stimulate insulin release from pancreatic beta cells in a glucose-dependent manner, meaning insulin secretion increases only when blood glucose levels are elevated, reducing hypoglycaemia risk.

• Suppressed glucagon release: They inhibit the secretion of glucagon from pancreatic alpha cells, thereby reducing hepatic glucose production when it is not needed.

• Delayed gastric emptying: Short-acting GLP-1 receptor agonists tend to slow gastric emptying more than long-acting agents, resulting in more gradual glucose absorption and reduced post-meal glucose spikes.

• Increased satiety: Central nervous system effects promote feelings of fullness, often leading to reduced caloric intake and weight loss.

DPP-4 inhibitors work through a more indirect mechanism. The DPP-4 enzyme rapidly degrades endogenous incretin hormones, particularly GLP-1 and GIP, limiting their glucose-lowering effects. By inhibiting this enzyme, gliptins increase the circulating levels and duration of action of naturally secreted incretins, typically increasing active GLP-1 concentrations by approximately two- to threefold. This enhancement produces:

• Glucose-dependent insulin secretion: Improved beta-cell responsiveness to elevated glucose levels.

• Modest glucagon suppression: Reduced inappropriate glucagon secretion during hyperglycaemia.

Importantly, both classes exhibit glucose-dependent mechanisms, meaning their effects diminish as blood glucose normalises, substantially reducing the risk of hypoglycaemia compared to sulphonylureas or insulin. This safety profile makes them particularly valuable in elderly patients or those at higher risk of dangerous glucose drops.

Key Differences Between Incretin Mimetics and DPP-4 Inhibitors

Whilst both medication classes target the incretin system, they differ substantially in their clinical characteristics, efficacy, and practical considerations, which influence prescribing decisions.

Route of administration represents an important distinction. Most incretin mimetics require subcutaneous injection, administered daily or weekly depending on the specific agent, though oral semaglutide (Rybelsus) is available. DPP-4 inhibitors are taken orally, typically once or twice daily. This difference significantly affects patient preference and adherence, with some individuals reluctant to use injectable therapies whilst others find the convenience of weekly injections preferable to daily tablets.

Important: Do not combine a GLP-1 receptor agonist with a DPP-4 inhibitor, as there is no added benefit from using both together.

Glucose-lowering efficacy varies considerably between the classes. Incretin mimetics generally produce greater reductions in HbA1c, typically lowering levels by 1.0–1.5% (11–16 mmol/mol), compared to DPP-4 inhibitors, which achieve more modest reductions of 0.5–0.8% (5–9 mmol/mol). This difference reflects the pharmacological distinction between direct receptor activation versus enhancement of endogenous hormone levels.

Weight effects differ markedly. Incretin mimetics consistently promote weight loss, with patients typically losing 2–6 kg over several months, making them particularly valuable for overweight or obese individuals with type 2 diabetes. In contrast, DPP-4 inhibitors are weight-neutral, neither causing weight gain nor loss.

Cardiovascular outcomes have emerged as an important consideration. Several incretin mimetics (liraglutide, semaglutide, dulaglutide) have demonstrated cardiovascular benefits in major trials, reducing the risk of cardiovascular death, myocardial infarction, and stroke in high-risk patients. Current evidence for DPP-4 inhibitors shows cardiovascular safety but no clear benefit. The MHRA has issued cautions regarding heart failure risk with saxagliptin and alogliptin in patients with existing heart failure or other risk factors; clinicians should carefully assess heart failure risk before prescribing these agents.

Cost considerations also differ, with incretin mimetics generally more expensive than DPP-4 inhibitors. Costs and formulary status vary; follow NICE and local formulary guidance. The choice between these agents should balance efficacy, patient preferences, comorbidities, and individual treatment goals in shared decision-making discussions.

Who Can Take These Diabetes Medications

NICE guidance (NG28: Type 2 diabetes in adults: management) provides clear recommendations regarding the appropriate use of incretin-based therapies in type 2 diabetes management, though individual patient factors determine suitability for each medication class.

General indications for both drug classes include adults with type 2 diabetes who have inadequate glycaemic control despite lifestyle modifications and first-line therapy with metformin. NICE typically recommends considering these agents when metformin alone proves insufficient, alongside SGLT2 inhibitors as key options for treatment intensification. The choice depends on individual patient factors, including cardiovascular risk, heart failure, chronic kidney disease, and treatment goals.

Incretin mimetics are particularly suitable for:

• Patients where weight loss would provide additional health benefits

• Individuals at high cardiovascular risk who may benefit from the cardioprotective effects of certain agents (liraglutide, semaglutide, dulaglutide)

• Patients wishing to avoid or delay insulin therapy

• Those requiring substantial HbA1c reductions to reach target levels

NICE NG28 specifies continuation criteria for GLP-1 receptor agonists in triple therapy: continue only if there is a beneficial metabolic response, defined as a reduction of at least 11 mmol/mol (1.0%) in HbA1c and weight loss of at least 3% of initial body weight at six months. Local pathways may vary; follow your diabetes team's advice.

DPP-4 inhibitors may be preferred for:

• Patients unable or unwilling to use injectable therapies

• Elderly individuals where the lower hypoglycaemia risk is particularly valuable

• Those at high risk of hypoglycaemia from other medications

• Patients requiring modest glycaemic improvements

• Individuals where weight neutrality is acceptable or desired

Important cautions and contraindications:

• Do not combine a GLP-1 receptor agonist with a DPP-4 inhibitor.

• Incretin mimetics should be avoided in type 1 diabetes, diabetic ketoacidosis, and severe gastrointestinal disease. Use with caution in patients with a history of pancreatitis or medullary thyroid carcinoma (or family history of multiple endocrine neoplasia type 2).

• Semaglutide (injectable) carries a warning regarding diabetic retinopathy complications in patients with pre-existing diabetic retinopathy; ensure retinal screening is up to date and seek prompt review if new or worsening visual symptoms occur.

• Renal impairment: Most DPP-4 inhibitors require dose adjustment in renal impairment; linagliptin does not. Exenatide is not recommended at low eGFR. Consult the Summary of Product Characteristics (SmPC) for agent-specific thresholds.

• Heart failure: Saxagliptin and alogliptin should be used with caution in patients with heart failure or risk factors for heart failure, as advised by the MHRA.

• Liver function: Vildagliptin requires periodic liver function test (LFT) monitoring as per the SmPC.

• Pregnancy and breastfeeding: Neither class is currently recommended during pregnancy or breastfeeding. Insulin remains the preferred option in these circumstances; specialist diabetes advice should be sought. Metformin may also be used in pregnancy per UK guidance.

Your diabetes team will assess your individual circumstances, including kidney function, heart health, and other medications, to determine the most appropriate treatment for you.

Common Side Effects and Safety Considerations

Understanding the adverse effect profiles of incretin mimetics and DPP-4 inhibitors enables appropriate patient counselling, monitoring, and early identification of potential complications.

Incretin mimetics commonly cause gastrointestinal disturbances, particularly during treatment initiation. These include:

• Nausea and vomiting: Affecting 20–40% of patients initially, though symptoms typically diminish over several weeks. Starting with lower doses and gradual titration helps minimise these effects. Maintain adequate hydration; if you experience persistent vomiting or diarrhoea, contact your GP, as dehydration may affect kidney function.

• Diarrhoea: Occurs in approximately 10–20% of patients, usually mild and transient.

• Reduced appetite: Whilst contributing to weight loss benefits, some patients find this troublesome.

• Injection site reactions: Mild erythema, itching, or discomfort may occur but rarely necessitate discontinuation.

More serious but rare concerns include:

• Acute pancreatitis: Seek immediate medical attention if you experience severe, persistent abdominal pain (which may radiate to the back), with or without vomiting. Whilst no definitive causal link has been established, caution is warranted in those with previous episodes.

• Gallbladder disease: GLP-1 receptor agonists may increase the risk of gallstones (cholelithiasis) and gallbladder inflammation (cholecystitis). Contact your GP promptly if you develop right-upper-quadrant abdominal pain, fever, or jaundice (yellowing of the skin or eyes).

• Diabetic retinopathy complications: Injectable semaglutide carries a warning regarding worsening of diabetic retinopathy in patients with pre-existing retinopathy. Report any new or worsening visual symptoms promptly.

• Thyroid concerns: Incretin mimetics carry warnings regarding thyroid C-cell tumours based on animal studies, though human relevance remains uncertain. They are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.

DPP-4 inhibitors generally demonstrate excellent tolerability with fewer gastrointestinal effects than incretin mimetics. Common issues include:

• Nasopharyngitis and upper respiratory tract infections: Reported more frequently than with placebo, though causality remains unclear.

• Headache: Mild and usually transient.

• Hypoglycaemia: Risk increases when combined with sulphonylureas or insulin, necessitating dose adjustments of these agents.

Serious adverse effects are uncommon but include:

• Acute pancreatitis: As with incretin mimetics, seek immediate medical attention for severe, persistent abdominal pain.

• Severe arthralgia (joint pain): May require discontinuation in some cases; report persistent or severe joint pain to your GP.

• Bullous pemphigoid: A rare blistering skin condition. Seek medical advice if you develop unexplained skin blistering.

• Heart failure: The MHRA has advised caution with saxagliptin and alogliptin in patients with existing heart failure or risk factors. Contact your GP if you experience new or worsening breathlessness, swelling of the ankles, or unusual tiredness.

• Angioedema: Rare but serious allergic reaction causing swelling of the face, lips, tongue, or throat. Seek immediate medical attention if this occurs. Risk may be higher if you also take an ACE inhibitor.

• Liver function monitoring: Vildagliptin requires periodic liver function tests as per the product information.

Patient safety advice for both classes:

• Contact your GP promptly if you experience severe abdominal pain, persistent vomiting, right-upper-quadrant pain, fever, jaundice, or signs of pancreatitis or gallbladder disease.

• Seek immediate medical attention for symptoms of serious allergic reactions (rash, swelling of the face or throat, breathing difficulties) or severe skin blistering.

• Monitor for hypoglycaemia when used with other glucose-lowering medications, particularly if experiencing unexplained sweating, tremor, confusion, or palpitations. Your doctor may need to adjust doses of sulphonylureas or insulin.

• Report any unusual symptoms such as severe joint pain, new or worsening breathlessness, ankle swelling, or visual changes.

• Report suspected side effects via the MHRA Yellow Card Scheme at https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store. Reporting helps improve the safety of medicines for everyone.

Regular monitoring through diabetes reviews, including HbA1c measurements, renal function tests, liver function tests (where indicated), and assessment of treatment response, ensures optimal safety and efficacy. The MHRA continues to monitor the safety profiles of these medications, and healthcare professionals should remain alert to emerging evidence regarding long-term outcomes.

Frequently Asked Questions