Incretin mimetics and SGLT2 inhibitors are two distinct classes of glucose-lowering medications that have revolutionised type 2 diabetes management in the UK. Incretin mimetics, such as semaglutide and dulaglutide, mimic natural hormones to enhance insulin secretion and reduce appetite. SGLT2 inhibitors, including dapagliflozin and empagliflozin, work by promoting urinary glucose excretion. Both classes offer benefits beyond glucose control, including cardiovascular and renal protection, and are increasingly used together for complementary effects. Understanding their mechanisms, benefits, and safety profiles helps patients and clinicians make informed treatment decisions aligned with NICE guidance and individual clinical needs.
Summary: Incretin mimetics and SGLT2 inhibitors are two distinct medication classes used in type 2 diabetes that work through independent mechanisms and can be combined for enhanced glucose control and organ protection.
- Incretin mimetics (GLP-1 receptor agonists) enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, and promote weight loss through appetite reduction.
- SGLT2 inhibitors block kidney glucose reabsorption, causing urinary glucose excretion independent of insulin, with additional cardiovascular and renal protective effects.
- Combining these classes provides additive HbA1c reduction without increasing hypoglycaemia risk when used together, as they work through completely different pathways.
- Both classes offer cardiovascular benefits and weight loss, with SGLT2 inhibitors particularly recommended for patients with chronic kidney disease or heart failure per NICE guidance.
- Main side effects include gastrointestinal symptoms with incretin mimetics and genital infections with SGLT2 inhibitors; rare serious risks include pancreatitis and euglycaemic ketoacidosis respectively.
- NICE NG28 recommends these agents as second-line options after metformin, with treatment selection guided by cardiovascular disease, chronic kidney disease, and patient preferences.
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What Are Incretin Mimetics and SGLT2 Inhibitors?
Incretin mimetics and SGLT2 inhibitors represent two distinct classes of glucose-lowering medications used primarily in the management of type 2 diabetes mellitus. These agents have transformed diabetes care over the past two decades, offering alternatives to traditional therapies such as metformin and sulphonylureas.
Incretin mimetics, also known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are medications that mimic the action of naturally occurring incretin hormones. Common examples licensed for type 2 diabetes in the UK include semaglutide (Ozempic), oral semaglutide (Rybelsus), dulaglutide (Trulicity), liraglutide (Victoza), and exenatide (Byetta, Bydureon). Injectable formulations are administered via subcutaneous injection, with dosing frequencies ranging from twice daily to once weekly, depending on the specific formulation. Oral semaglutide is taken once daily. (Note: Wegovy and Saxenda contain semaglutide and liraglutide respectively, but are licensed for weight management, not for type 2 diabetes treatment.) Tirzepatide, a dual GIP/GLP-1 receptor agonist, is also now licensed for type 2 diabetes in the UK.
SGLT2 inhibitors, or sodium-glucose co-transporter-2 inhibitors, are oral medications that work through a completely different mechanism. This class includes dapagliflozin (Forxiga), empagliflozin (Jardiance), and canagliflozin (Invokana). These tablets are typically taken once daily and have gained recognition not only for glucose control but also for cardiovascular and renal protective effects.
Both medication classes are licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) for use in the United Kingdom. They are increasingly prescribed either as monotherapy when metformin is contraindicated or not tolerated, or as add-on therapy to existing glucose-lowering regimens. NICE guidance provides specific criteria for their use, particularly for GLP-1 receptor agonists, which may be more restrictive than the marketing authorisations. Understanding how these medications work and their respective benefits helps patients and healthcare professionals make informed treatment decisions aligned with individual clinical needs and preferences.
How These Medications Work to Control Blood Sugar
The mechanisms of action for incretin mimetics and SGLT2 inhibitors are fundamentally different, which explains why they may be used together for complementary glucose-lowering effects.
Incretin mimetics work by mimicking the action of glucagon-like peptide-1 (GLP-1), a naturally occurring hormone released from the intestine in response to food intake. These medications bind to GLP-1 receptors on pancreatic beta cells, stimulating insulin secretion in a glucose-dependent manner—meaning insulin is only released when blood glucose levels are elevated. This glucose-dependent mechanism significantly reduces the risk of hypoglycaemia compared to medications like sulphonylureas, when used alone or with metformin. Additionally, incretin mimetics suppress glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. They also slow gastric emptying, which moderates the post-meal rise in blood glucose, and act on appetite centres in the brain to promote satiety, often resulting in weight loss.
SGLT2 inhibitors operate through an entirely different pathway that is independent of insulin. These medications block the sodium-glucose co-transporter-2 protein in the proximal tubule of the kidney, which is responsible for reabsorbing approximately 90% of filtered glucose back into the bloodstream. By inhibiting this transporter, SGLT2 inhibitors cause excess glucose to be excreted in the urine (glycosuria). The amount of glucose excreted varies with blood glucose levels and kidney function, but typically ranges from 60–80 grams daily in people with well-controlled diabetes. This mechanism also results in modest calorie loss and mild diuretic effects, contributing to small reductions in blood pressure and body weight.
Because these two classes work through completely independent mechanisms—one enhancing insulin secretion and reducing appetite, the other promoting urinary glucose excretion—they can be combined to achieve additive glucose-lowering effects without increasing hypoglycaemia risk when used together. However, if either class is combined with sulphonylureas or insulin, dose reductions of those medications may be needed to minimise the risk of hypoglycaemia.
Benefits of Combining Incretin Mimetics and SGLT2 Inhibitors
The combination of incretin mimetics and SGLT2 inhibitors offers several complementary benefits that extend beyond glucose control alone, addressing multiple aspects of type 2 diabetes management and its associated complications.
Enhanced glycaemic control is achieved through the additive effects of two independent mechanisms. Clinical trials such as DURATION-8, AWARD-10, and SUSTAIN-9 have demonstrated that combining these agents can produce meaningful HbA1c reductions from baseline, often enabling patients to reach individualised glycaemic targets without requiring insulin therapy. The degree of HbA1c reduction depends on baseline levels and individual response, but reductions of 1.0–2.0% (11–22 mmol/mol) have been observed in clinical studies. This is particularly valuable for patients who have not achieved adequate control with metformin alone or with dual therapy.
Cardiovascular protection represents a significant advantage of this combination. Multiple cardiovascular outcome trials have demonstrated that certain GLP-1 receptor agonists (including semaglutide in SUSTAIN-6, dulaglutide in REWIND, and liraglutide in LEADER) reduce the risk of major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular death. Similarly, SGLT2 inhibitors (particularly empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS) have shown cardiovascular benefits. When used together in patients with established cardiovascular disease or multiple risk factors, these medications may provide complementary cardioprotective effects, though dedicated cardiovascular outcome trials of the combination have not been conducted.
Weight management is another key benefit, as both classes typically promote weight loss rather than weight gain. The degree of weight loss varies by agent and dose: GLP-1 receptor agonists can produce weight reductions averaging 2–6 kg, with higher-dose semaglutide achieving greater losses, whilst SGLT2 inhibitors typically result in 2–3 kg weight loss. This contrasts favourably with insulin and sulphonylureas, which often cause weight gain.
Renal protection has been demonstrated with SGLT2 inhibitors, which slow the progression of diabetic kidney disease and reduce the risk of end-stage renal failure. Some evidence suggests GLP-1 receptor agonists may also offer renal benefits. For patients with type 2 diabetes and chronic kidney disease, this combination may provide comprehensive organ protection whilst maintaining glucose control.
Side Effects and Safety Considerations
Whilst incretin mimetics and SGLT2 inhibitors are generally well-tolerated, patients and healthcare professionals should be aware of their distinct side effect profiles and important safety considerations.
Incretin mimetic side effects are predominantly gastrointestinal. Nausea, vomiting, diarrhoea, and abdominal discomfort affect 20–40% of patients, particularly during treatment initiation or dose escalation. These effects typically diminish over 4–8 weeks. To minimise gastrointestinal symptoms, treatment should be initiated at the lowest dose with gradual titration. Patients should be advised to eat smaller, more frequent meals and avoid high-fat foods. Rare but serious adverse effects include acute pancreatitis—patients should seek immediate medical attention for severe, persistent abdominal pain radiating to the back. GLP-1 receptor agonists may increase the risk of gallbladder disease; patients should report symptoms such as upper abdominal pain, particularly after meals. Rapid improvement in blood glucose control, particularly with semaglutide, has been associated with worsening of diabetic retinopathy in some patients; those with pre-existing retinopathy should be monitored appropriately. Based on animal studies, there is a theoretical risk of medullary thyroid carcinoma. Whilst this is not a formal contraindication in UK prescribing information, patients should be advised to seek medical review if they develop symptoms such as a lump in the neck, difficulty swallowing, or persistent hoarseness.
SGLT2 inhibitor side effects relate primarily to their mechanism of increasing urinary glucose excretion. Genital mycotic infections (thrush) occur in 10–15% of patients, particularly women, due to glucose in the urine creating a favourable environment for fungal growth. These infections are usually mild and respond to standard antifungal treatments. Volume depletion may occur, particularly in elderly patients or those taking diuretics, potentially causing dizziness or postural hypotension. Patients should maintain adequate hydration. A rare but serious complication is euglycaemic diabetic ketoacidosis—a form of ketoacidosis that can occur even when blood glucose levels are not markedly elevated. The MHRA advises that SGLT2 inhibitors should be stopped temporarily during periods of prolonged fasting, major surgery, or acute serious medical illness. Specifically, these medications should be withheld at least 3 days before planned major surgery or procedures requiring prolonged fasting (4 days for ertugliflozin, though this agent has limited UK availability). Patients should be educated to test for ketones (preferably blood ketones) if feeling unwell and to seek urgent medical attention if ketones are elevated or if they experience symptoms of ketoacidosis: nausea, vomiting, abdominal pain, unusual fatigue, or difficulty breathing. Another rare but serious risk is Fournier's gangrene (necrotising fasciitis of the perineum). Patients should seek emergency medical care if they develop severe pain, tenderness, redness, or swelling in the genital or perineal area, accompanied by fever or feeling generally unwell.
When combining these medications, the side effect profiles remain distinct, and there is no evidence of synergistic adverse effects. However, if either class is combined with insulin or sulphonylureas, dose reductions of those medications are usually needed to reduce the risk of hypoglycaemia. Patients should be counselled about maintaining adequate hydration, adhering to sick-day rules (temporarily stopping SGLT2 inhibitors when acutely unwell), and recognising warning signs requiring medical review. Suspected side effects should be reported via the MHRA Yellow Card Scheme (yellowcard.mhra.gov.uk).
Who Should Consider These Treatments?
The decision to prescribe incretin mimetics, SGLT2 inhibitors, or their combination should be individualised based on patient characteristics, comorbidities, treatment goals, and preferences, in line with contemporary diabetes management principles. These medications are licensed for type 2 diabetes only and are not indicated for type 1 diabetes, where SGLT2 inhibitors in particular carry an increased risk of diabetic ketoacidosis.
Ideal candidates for incretin mimetics include patients with type 2 diabetes who have not achieved glycaemic targets with metformin alone, particularly those who are overweight or obese and would benefit from weight loss. NICE guidance (NG28) specifies criteria for GLP-1 receptor agonist use, including consideration of body mass index and the presence of weight-related problems. These agents are especially valuable for patients with established atherosclerotic cardiovascular disease or at high cardiovascular risk, given their proven cardioprotective effects in clinical trials. Patients concerned about hypoglycaemia risk may prefer incretin mimetics over sulphonylureas or insulin. Injectable formulations require subcutaneous injection, so patient willingness to self-inject and manual dexterity are important considerations; oral semaglutide offers an alternative for those preferring tablets.
Ideal candidates for SGLT2 inhibitors include patients with type 2 diabetes and chronic kidney disease. NICE guidance (NG28, NG203) recommends SGLT2 inhibitors for adults with type 2 diabetes and an albumin:creatinine ratio (ACR) of 30 mg/mmol or more, and an estimated glomerular filtration rate (eGFR) of at least 20 mL/min/1.73 m², to slow the progression of kidney disease. They are also recommended for patients with heart failure, with benefits demonstrated across the spectrum of ejection fractions (heart failure with reduced, mildly reduced, and preserved ejection fraction). Patients with established atherosclerotic cardiovascular disease may benefit from the cardioprotective effects. The oral route of administration makes SGLT2 inhibitors attractive for patients who prefer tablets to injections. NICE guidance supports early use of SGLT2 inhibitors in people with type 2 diabetes and high cardiovascular or renal risk, sometimes irrespective of baseline HbA1c.
Combination therapy with both classes may be considered for patients requiring substantial HbA1c reduction who have not achieved targets with metformin plus one additional agent, subject to NICE criteria for GLP-1 receptor agonist use. This approach is particularly appropriate for patients with both cardiovascular disease and chronic kidney disease, potentially offering dual organ protection. Patients motivated to achieve significant weight loss may benefit from the combined weight-reducing effects of both medication classes.
Contraindications and cautions must be considered. SGLT2 inhibitors should be used cautiously in patients with recurrent genital infections or those at risk of volume depletion, and are contraindicated in diabetic ketoacidosis. Renal function thresholds for initiation and continuation vary by agent and indication; prescribers should consult individual Summaries of Product Characteristics (SmPCs) for specific guidance. GLP-1 receptor agonists generally do not require dose adjustment for renal impairment, though exenatide is an exception and should be used with caution in moderate to severe renal impairment. Both classes should generally be avoided in pregnancy and breastfeeding; women planning pregnancy should discuss alternative treatment options with their healthcare team. Patients should consult their diabetes team or GP before starting these medications to ensure suitability.
NHS Prescribing and NICE Guidance
The National Institute for Health and Care Excellence (NICE) provides comprehensive guidance on the use of incretin mimetics and SGLT2 inhibitors within NHS diabetes care pathways, reflecting the evolving evidence base for these medications.
NICE guideline NG28 (Type 2 diabetes in adults: management, updated 2022) recommends a stepwise approach to glucose-lowering therapy. Following lifestyle modification, metformin remains the first-line pharmacological treatment for most patients. When metformin monotherapy does not achieve individualised HbA1c targets, NICE recommends considering dual therapy. At this stage, either an SGLT2 inhibitor or a GLP-1 receptor agonist may be added, with the choice influenced by patient factors including cardiovascular disease, heart failure, chronic kidney disease, and body weight considerations.
Cardiovascular and renal considerations are now central to treatment selection. NICE specifically recommends SGLT2 inhibitors for patients with type 2 diabetes and chronic kidney disease (ACR ≥30 mg/mmol and eGFR ≥20 mL/min/1.73 m²) to slow disease progression, as detailed in NG28 and NG203 (Chronic kidney disease: assessment and management). For patients with established cardiovascular disease, NICE suggests considering medications with proven cardiovascular benefit, which includes both certain GLP-1 receptor agonists and SGLT2 inhibitors. NICE technology appraisals (including TA775 for dapagliflozin in CKD, TA679 for dapagliflozin in heart failure with reduced ejection fraction, and TA773 for empagliflozin in heart failure with preserved or mildly reduced ejection fraction) provide further detail on cardiorenal indications. The 2022 NICE guideline updates emphasise that cardiovascular and renal protection should be prioritised alongside glucose control, and SGLT2 inhibitors may be initiated early in people with high cardiovascular or renal risk.
Triple therapy may be considered when dual therapy fails to achieve glycaemic targets. NICE NG28 allows for the addition of a third glucose-lowering medication, which can include the combination of metformin, an SGLT2 inhibitor, and a GLP-1 receptor agonist, provided the criteria for GLP-1 receptor agonist use are met. These criteria include consideration of body mass index (BMI) and the presence of weight-related problems. This combination is increasingly recognised as an effective insulin-sparing strategy that addresses multiple pathophysiological defects in type 2 diabetes whilst providing cardiovascular and renal benefits.
NHS prescribing considerations include cost-effectiveness assessments and local formulary restrictions. Whilst both medication classes are available on NHS prescription, some Integrated Care Boards (ICBs) or Integrated Care Systems (ICSs) may have preferred agents within each class based on cost and local prescribing agreements. Patients should be reviewed regularly (typically every 3–6 months) to assess treatment response, tolerability, and ongoing appropriateness. Healthcare professionals should ensure patients receive appropriate education about medication administration, side effect recognition, and sick-day rules, particularly regarding temporary discontinuation of SGLT2 inhibitors (at least 3 days before major surgery or during acute serious illness) to reduce ketoacidosis risk. Patients should be advised to report suspected adverse reactions via the MHRA Yellow Card Scheme.
Frequently Asked Questions
Can incretin mimetics and SGLT2 inhibitors be used together safely?
Yes, these medications can be safely combined as they work through independent mechanisms—one enhancing insulin secretion and the other promoting urinary glucose excretion. This combination provides additive glucose-lowering effects without increasing hypoglycaemia risk when used together, though dose adjustments may be needed if combined with insulin or sulphonylureas.
Which patients benefit most from combining these two medication classes?
Patients with type 2 diabetes who have not achieved glycaemic targets with metformin plus one agent benefit most, particularly those with both cardiovascular disease and chronic kidney disease. This combination is especially valuable for patients seeking substantial HbA1c reduction whilst avoiding insulin therapy and benefiting from dual organ protection.
What are the most important safety precautions when taking SGLT2 inhibitors?
SGLT2 inhibitors should be stopped at least 3 days before major surgery or during acute serious illness to reduce the risk of euglycaemic diabetic ketoacidosis. Patients should maintain adequate hydration, monitor for genital infections, and seek urgent medical attention if they develop symptoms of ketoacidosis such as nausea, vomiting, abdominal pain, or difficulty breathing, even with normal blood glucose levels.
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