Sodium-glucose co-transporter-2 inhibitors (SGLT2i), also known as gliflozins, inhibit glucose reabsorption by blocking the SGLT2 protein in the proximal tubules in the kidney, increasing urinary glucose excretion and leading to reduced blood glucose levels.1
The SGLT2i agents currently available in the UK are canaglifozin, dapagliflozin, empagliflozin and ertugliflozin.2 All are once daily dosing, which ideally should be administered in the morning due to the highly possible increase in voiding caused by the glycosuria.1
The current National Institute for Health and Care Excellence (NICE) type 2 diabetes guideline recommends the use of SGLT2i as dual therapy with metformin (or as monotherapy if metformin is not tolerated/contraindicated) in those with type 2 diabetes with established or high risk of atherosclerotic cardiovascular disease (ASCVD), and in combination with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in those with chronic kidney disease (CKD).
SGLT2i can also be used as monotherapy in those who are not at high risk of ASCVD and as dual or triple therapy if the other glucose lowering agents do not achieve the patient’s individualised HbA1c target.3
It is important to consider safety and tolerability before a SGLT2i is used. Table 1 outlines the clinical situations where a SGLT2i can be prescribed safely, when caution needs to be exercised or when a SGLT2i should be avoided.
|Table 1: Prescribing SGLT2i therapy in type 2 diabetes4|
|Low risk||Moderate risk (use with caution)||High risk (do not initiate SGLT2i)|
Along with their moderate-to-high glucose lowering effects, SGLT2i have been demonstrated to also have beneficial effects on blood pressure and weight reduction. Furthermore, the cardiovascular outcome trials and studies in people with renal disease and heart failure have shown significant benefits in these co-morbidities, which are independent of glucose lowering in people with and without type 2 diabetes.5
SGLT2i are therefore also licensed for use in heart failure and chronic kidney disease with or without type 2 diabetes.5 Table 2 depicts the licensing of SGLT2i in the UK outside of type 2 diabetes.5
|Table 2: Extra indications of SGLT2i5|
|SGLT2i||Heart failure||Chronic kidney disease/diabetic kidney disease|
|–||Diabetic kidney disease only|
|Yes||With or without type 2 diabetes|
Looking at the risks
Although SGLT2i do not cause hypoglycaemia, there is an increased risk of this happening if taken in combination with insulin and/or a sulfonylurea. The dose of insulin and/or sulfonylurea may need to be reduced to minimise the risk of hypoglycaemia.5
The Medicines and Healthcare products Regulatory Agency (MHRA) and European Medicines Agency (EMA) have confirmed diabetic ketoacidosis (DKA) as a rare risk for the SGLT2i drug class.6 DKA may also present with relatively normal glucose levels (euglycaemic ketoacidosis).5
The regulators’ review recommended that healthcare professionals should inform patients on SGLT2i of the risks of DKA and counsel them on risk factors and the actions to take in case of signs and symptoms. The SGLT2i should be discontinued when DKA has been diagnosed.6
The risk of DKA is higher if a patient is relatively insulin deficient (e.g. patients with late-onset autoimmune diabetes who have been misdiagnosed as having type 2 diabetes); there are sudden reductions in insulin dose; there is an increased requirement for insulin (due to illness, surgery or alcohol abuse); or conditions occur that restrict food intake (particularly carbohydrate consumption) or lead to severe dehydration.5
An increased incidence of lower limb amputation (mainly toes) was seen in the CANVAS (canagliflozin) trial. This higher incidence may have been due to the fact that the trial recruited individuals with a history of peripheral arterial disease and amputations, which may have increased the incidence of lower limb amputations in this cohort.5
Although evidence does not show an increased risk for the other available SGLT2i, the EMA has advised caution in using SGLT2i in those at high risk of lower limb amputation as a class effect cannot be ruled out. While the risk of lower limb amputation is low, it is still higher in those with a previous amputation.
SGLT2i should be avoided in those with active foot ulceration or previous amputation. Preventive foot care is important for all patients with type 2 diabetes7.
It is important to note that the crude number of lower limb amputation events recorded in major cardiovascular outcome trials was relatively low when compared with the number of people who demonstrated improved outcomes, such as a reduced risk of heart failure or all-cause death.5
The CANVAS trial also demonstrated a slight increase in fracture incidence but again this was not replicated in other SGLT2i trials. It is thought the fractures occurred early in treatment and may have been linked to increased falls due to volume depletion and hypotension.5
What to advise those individuals on SGLT2i drugs
Glycosuria can lead to increased urination, which is regarded as an expected renal response to increased urinary excretion of glucose. However, hypovolaemia can occur if there is no increased fluid intake. Advise those on SGLT2i to drink at least two to three litres of fluid daily.8
If a patient is unable to eat or drink, or has persistent vomiting or diarrhoea, then the SADMAN drugs (SGLT2i, ACE inhibitors, Diuretics, Metformin, Angiotensin-2 receptor blockers and NSAIDs) should be temporarily stopped and restarted 24-48 hours after recovery from illness.
Advise the patient to keep hydrated (drink two to three litres of fluid per day) and eat little and often. If they are not able to eat normally, meals should be replaced with high carbohydrate snacks or drinks.
They should be advised to keep taking insulin and all other diabetes medicines (apart from metformin, SGLT2i and GLP-1 receptor agonists) even if they are not eating as blood glucose levels are likely to rise during illness.
It is recommended to check blood glucose levels every four hours and the doses of insulin and/or sulfonylurea should be guided by their blood glucose profile. Contact the patient’s diabetes team if unsure what to do.5
The patient should seek medical advice if they experience the following DKA symptoms: nausea, vomiting, abdominal pain, generalised malaise and shortness of breath, even if their blood glucose levels are not elevated.6
Genital thrush infections are more common early in treatment. To mitigate the risk, personal hygiene advice should be advised at the point of prescribing. Most patients can continue SGLT2i treatment. UTIs are relatively rare and can be managed with standard antibiotics. If the genital thrush/UTI infections are recurrent, SGLT2i treatment should be stopped.5
Advice should be given on preventative foot care – inspect feet regularly, report wounds, discolouration or pain, and stay well hydrated.7
1. Fonseca-Correa JI and Correa-Rotter R. (2021). Sodium-glucose cotransporter 2 inhibitors mechanisms of action: a review. Frontiers in Medicine, 8. doi:10.3389/fmed.2021.777861
3. Overview: Type 2 diabetes in adults: Management: Guidance (2022).
4. Brown P. (2021) How to use SGLT2 inhibitors safely and effectively. Diabetes & Primary Care 23: 5-74
5. Wilding J, Fernando K, Milne N. et al. SGLT2 Inhibitors in Type 2 Diabetes Management: Key Evidence and Implications for Clinical Practice. Diabetes Ther 9, 1757-1773 (2018). doi.org/10.1007/s13300-018-0471-8
6. Medicines and Healthcare products Regulatory Agency (2020) SGLT2 inhibitors: Monitor ketones in blood during treatment interruption for surgical procedures or acute serious medical illness. GOV.UK.
8. Evans M, Morgan AR, Bain SC, Davies S, Dashora U, Sinha S, Seidu S, Patel DC, Beba H, Strain WD. Defining the Role of SGLT2 Inhibitors in Primary Care: Time to Think Differently. Diabetes Ther. 2022 May; 13(5):889-911. doi: 10.1007/s13300-022-01242-y