SGLT2 inhibitors for type 2 diabetes represent a transformative class of oral medications that work by promoting glucose excretion through the kidneys, rather than relying on insulin. Agents such as dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin are licensed in the UK and recommended by NICE, particularly for patients with cardiovascular disease, chronic kidney disease, or heart failure. Beyond lowering blood glucose, these medicines offer proven cardiovascular and renal protection, reduce hospitalisation for heart failure, and support modest weight loss. Understanding how SGLT2 inhibitors work, who can benefit, and their safety profile helps patients and clinicians make informed treatment decisions aligned with current UK guidance.

What Are SGLT2 Inhibitors and How Do They Work?

Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a modern class of oral medications used in the management of type 2 diabetes mellitus. These agents include dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin, all of which are licensed in the UK. NICE recommends SGLT2 inhibitors for specific patient groups, particularly those with established cardiovascular disease, chronic kidney disease, or heart failure.

Unlike traditional diabetes medications that work by increasing insulin secretion or improving insulin sensitivity, SGLT2 inhibitors employ a unique mechanism of action. They work by blocking the SGLT2 protein in the proximal tubules of the kidneys, which is responsible for reabsorbing approximately 90% of filtered glucose back into the bloodstream. By inhibiting this transporter, SGLT2 inhibitors promote urinary glucose excretion (glucosuria), effectively lowering blood glucose levels independently of insulin.

This insulin-independent mechanism offers several advantages. Firstly, it reduces the risk of hypoglycaemia when used as monotherapy or with metformin. Secondly, the loss of glucose in urine results in a modest calorie deficit, typically leading to weight loss of 2–3 kg over several months—a beneficial effect for many people with type 2 diabetes who are overweight. Additionally, the mild osmotic diuresis (increased urine production) caused by glucose excretion can contribute to modest reductions in blood pressure.

Large clinical trials have demonstrated that SGLT2 inhibitors provide cardiovascular and renal protective effects beyond glucose control, which has significantly expanded their role in diabetes management. These benefits have been consistently observed across multiple studies, though the precise mechanisms remain under investigation and may include improvements in cardiac metabolism, reduction in arterial stiffness, and decreased pressure within the kidney's filtering units.

References: NICE NG28 (Type 2 diabetes in adults); electronic Medicines Compendium (eMC) Summaries of Product Characteristics for dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin; EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58 trials.

Common Side Effects and Safety Considerations

As with all medications, SGLT2 inhibitors carry a recognised side effect profile that patients and healthcare professionals should understand. The most frequently reported adverse effects relate directly to the drug's mechanism of increasing urinary glucose excretion.

Genital fungal infections are the most common side effect, occurring in approximately 10–15% of patients. The presence of glucose in urine creates a favourable environment for fungal growth. Women are particularly susceptible to vulvovaginal candidiasis (thrush), whilst men may experience balanitis. Urinary tract infections may also occur, though the risk increase is small and varies between individual agents. Most infections respond well to standard antimicrobial treatment, and the medication can usually be continued. Maintaining good personal hygiene and adequate hydration can help reduce infection risk.

The osmotic diuretic effect may cause increased urination (polyuria), particularly when treatment is initiated. This typically improves after the first few weeks. Patients should be advised to maintain adequate fluid intake and may need to adjust the timing of their dose if night-time urination becomes problematic.

A rare but serious adverse effect is diabetic ketoacidosis (DKA), which can occur even when blood glucose levels are not markedly elevated (euglycaemic DKA). Warning signs include:

• Nausea and vomiting

• Abdominal pain

• Unusual fatigue

• Difficulty breathing

• Confusion

Patients should be counselled to stop their SGLT2 inhibitor temporarily during acute illness, if they are unable to eat or drink normally, or before major surgery (typically 3 days beforehand), as these situations increase DKA risk. If you feel unwell or develop symptoms suggestive of DKA, check your blood ketones if possible and seek immediate medical attention. Avoid very-low-carbohydrate or ketogenic diets whilst taking these medicines, and do not reduce your insulin dose abruptly without medical advice. Restart your SGLT2 inhibitor only when you are clinically stable, eating and drinking normally, and your ketones are normal.

Fournier's gangrene, a rare necrotising infection of the genital area, has been reported with SGLT2 inhibitor use. Patients experiencing genital pain, tenderness, redness, or swelling accompanied by fever should seek urgent medical assessment.

Amputation risk (particularly affecting the toes) and bone fractures have been observed mainly with canagliflozin in clinical trials. If you are taking canagliflozin, maintain good foot care, inspect your feet regularly, and seek prompt medical review if you develop new foot ulcers, infections, or pain.

Hypoglycaemia risk is low when SGLT2 inhibitors are used alone or with metformin. However, if you are also taking insulin or a sulfonylurea (such as gliclazide), your risk of low blood sugar increases, and your doctor may need to reduce the dose of these other medicines.

Other considerations include volume depletion (particularly in elderly patients or those taking diuretics), and caution in moderate to severe liver impairment (specific guidance varies by agent—consult your doctor or the medicine's Summary of Product Characteristics).

Pregnancy and breastfeeding: SGLT2 inhibitors are not recommended during pregnancy or breastfeeding. If you are planning a pregnancy, pregnant, or breastfeeding, discuss alternative treatments with your healthcare team.

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed here. You can also report side effects directly via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

References: MHRA Drug Safety Updates on SGLT2 inhibitors and diabetic ketoacidosis, Fournier's gangrene, and perioperative advice; eMC Summaries of Product Characteristics; NHS medicines pages for dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin.

Who Can Take SGLT2 Inhibitors: Eligibility and Contraindications

NICE guidance provides clear recommendations regarding the appropriate use of SGLT2 inhibitors in type 2 diabetes management. These medications are often considered alongside metformin, or when metformin is contraindicated or not tolerated. Importantly, in certain patient groups, SGLT2 inhibitors may be offered early in treatment or even irrespective of current blood glucose control.

SGLT2 inhibitors are particularly recommended for patients with:

• Established cardiovascular disease (such as previous heart attack, stroke, or peripheral arterial disease) or high cardiovascular risk

• Chronic kidney disease (CKD), where they slow disease progression and reduce the risk of kidney failure

• Heart failure (with reduced or preserved ejection fraction), where they have demonstrated significant reductions in hospitalisation and mortality

• A need to minimise hypoglycaemia risk

• Obesity, where weight loss would be beneficial

In people with established cardiovascular disease, chronic kidney disease, or heart failure, NICE recommends offering an SGLT2 inhibitor (often alongside metformin or independent of HbA1c level) using agents with the relevant UK-licensed indications. The choice of specific SGLT2 inhibitor depends on individual patient characteristics, licensed indications, and the clinical condition being treated. For example, dapagliflozin and empagliflozin have robust evidence and UK licences for heart failure and chronic kidney disease (with or without diabetes), whilst canagliflozin also demonstrates cardiovascular and renal benefits.

When SGLT2 inhibitors should not be used:

SGLT2 inhibitors are not indicated for:

• Type 1 diabetes (except in specific research settings)

• Treatment of diabetic ketoacidosis

Caution and specialist advice are needed in:

• Severe renal impairment: Specific eGFR thresholds for starting or continuing treatment vary by agent and indication. For glycaemic control, most agents are not initiated below eGFR 60 mL/min/1.73 m² and may be continued to lower thresholds (often 45 or 30 mL/min/1.73 m²). For heart failure or chronic kidney disease indications, some agents (such as dapagliflozin and empagliflozin) can be started at eGFR ≥20 or ≥25 mL/min/1.73 m². Always check the Summary of Product Characteristics for the specific agent and indication.

• Recurrent genital or urinary tract infections

• Increased risk of volume depletion (elderly patients, those on loop diuretics, or with low blood pressure)

• History of lower limb amputation, peripheral vascular disease, or diabetic foot problems (particularly for canagliflozin)

• Severe hepatic impairment (moderate impairment may not require dose adjustment—consult the Summary of Product Characteristics)

• Pregnancy and breastfeeding (not recommended; discuss alternatives with your healthcare team)

Renal function should be assessed before initiating treatment and monitored regularly thereafter. Glycaemic efficacy diminishes with declining kidney function, though cardiovascular and renal benefits may persist at lower eGFR depending on the agent and indication. Dose adjustments or discontinuation may be necessary if eGFR falls below specified thresholds.

Patients should be counselled about sick day rules, including temporary cessation during acute illness or before major surgery (typically stop 3 days beforehand), and the importance of maintaining adequate hydration. A thorough discussion of benefits and risks enables shared decision-making aligned with individual patient preferences and clinical circumstances.

References: NICE NG28 (Type 2 diabetes in adults); NICE NG106 (Chronic heart failure in adults); NICE NG203 (Chronic kidney disease); NICE Technology Appraisals TA679, TA773 (heart failure), TA775, TA942 (chronic kidney disease); eMC Summaries of Product Characteristics for individual agents.

Benefits and Effectiveness of SGLT2 Inhibitors in Type 2 Diabetes

The therapeutic benefits of SGLT2 inhibitors extend considerably beyond their glucose-lowering effects, making them an increasingly important component of type 2 diabetes management strategies.

Glycaemic control: SGLT2 inhibitors typically reduce HbA1c by approximately 0.5–1.0% (5–11 mmol/mol) when added to existing therapy. Whilst this reduction is modest compared to some other agents, the glucose-lowering effect is sustained over time and carries a low risk of hypoglycaemia when used alone or with metformin. The insulin-independent mechanism means they remain effective across a broad range of diabetes severity, though glycaemic efficacy does decline with worsening renal function.

Cardiovascular benefits: Landmark cardiovascular outcome trials have demonstrated that SGLT2 inhibitors significantly reduce the risk of major adverse cardiovascular events in patients with established cardiovascular disease. In the EMPA-REG OUTCOME trial, empagliflozin reduced cardiovascular death by 38% in high-risk patients. In the CANVAS programme, canagliflozin reduced major adverse cardiovascular events (heart attack, stroke, or cardiovascular death) by approximately 14%, though the reduction in cardiovascular death alone was not statistically significant. The DECLARE-TIMI 58 trial with dapagliflozin confirmed cardiovascular safety and benefits in a broader population. These agents also consistently reduce hospitalisation for heart failure by 30–35%, a benefit observed even in patients without prior heart failure and across the spectrum of ejection fraction (reduced and preserved).

Heart failure benefits: In dedicated heart failure trials (DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved), SGLT2 inhibitors have demonstrated significant reductions in cardiovascular death and heart failure hospitalisation in people with heart failure, regardless of diabetes status. These benefits have led to UK licensing and NICE recommendations for dapagliflozin and empagliflozin in heart failure.

Renal protection: SGLT2 inhibitors slow the progression of diabetic kidney disease and chronic kidney disease more broadly. The CREDENCE trial showed canagliflozin reduced the composite renal outcome (dialysis, transplantation, or sustained eGFR decline) by 30% in patients with type 2 diabetes and chronic kidney disease. Subsequent trials (DAPA-CKD, EMPA-KIDNEY) confirmed that dapagliflozin and empagliflozin provide renal protection in people with chronic kidney disease, with or without diabetes. Both agents now have UK licences for chronic kidney disease management regardless of diabetes status.

Weight and blood pressure: Patients typically experience weight loss of 2–3 kg and systolic blood pressure reductions of 3–5 mmHg—both beneficial for cardiovascular risk reduction.

NICE recommendations support the use of SGLT2 inhibitors in people with type 2 diabetes, particularly those with established or high-risk cardiovascular disease, chronic kidney disease, or heart failure. In these patient groups, an SGLT2 inhibitor should be offered (often alongside metformin or irrespective of HbA1c level), using agents with the relevant UK-licensed indications. The choice between SGLT2 inhibitors and other agents (such as GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas) should be individualised based on patient characteristics, comorbidities, and treatment goals.

Regular monitoring remains essential, including HbA1c assessment every 3–6 months, renal function testing before starting treatment and at least annually thereafter (or more frequently if eGFR is declining or below 60 mL/min/1.73 m²), and ongoing review of cardiovascular risk factors. Patients should be encouraged to maintain healthy lifestyle measures alongside pharmacotherapy for optimal diabetes management.

References: NICE NG28 (Type 2 diabetes in adults); NICE NG106 (Chronic heart failure); NICE NG203 (Chronic kidney disease); NICE Technology Appraisals TA679, TA773, TA775, TA942; EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, CREDENCE, DAPA-CKD, EMPA-KIDNEY trials; eMC Summaries of Product Characteristics.

Frequently Asked Questions