This article outlines the place of sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy in type 2 diabetes, while highlighting relevant cautions, contraindications and side-effects, with the aim of supporting safe prescribing and use of SGLT2 inhibitors for glycaemic control in adults with type 2 diabetes. After reading this article, the reader should:
- Understand the mechanism of action of SGLT2 inhibitors
- Understand SGLT2 inhibitors' place in therapy of for type 2 diabetes and which people with diabetes may benefit from SGLT2 inhibitor therapy
- Be aware of the cautions, contraindications, side-effects and monitoring requirements for SGLT2 inhibitors
- Be aware of prescribing considerations and patient information when initiating SGLT2 therapy.
What are SGLT2 inhibitors?
SGLT2 inhibitors, sometimes also referred to as ‘gliflozins’ or ‘flozins’ are an established class of medications, which are licensed for the treatment of (Table 1):
Table 1. SGLT2 inhibitor indications and licence status
| SGLT2 inhibitor | Indication and UK licence status | |||
|---|---|---|---|---|
| T2DM | HFrEF | HFpEF | CKD | |
| Canagliflozin | Licensed | Not licensed | Not licensed | Not licensed |
| Dapagliflozin | Licensed | Licensed | Not licensed | Licensed |
| Empagliflozin | Licensed | Licensed | Licensed | Not licensed |
| Ertugliflozin | Licensed | Not licensed | Not licensed | Not licensed |
- Insufficiently controlled type 2 diabetes (National Institute for Health and Care Excellence (NICE), 2022a)
- Symptomatic chronic heart failure with reduced (HFrEF) or preserved ejection (HFpEF) fraction (with or without type 2 diabetes) (NICE, 2021; 2022b)
- Chronic kidney disease (CKD) (with or without type 2 diabetes) (NICE, 2022c).
The class of SGLT2 inhibitors includes: canagliflozin, dapagliflozin, empagliflozin and ertugliflozin (Joint Formulary Committee, 2022). It is important to note not every drug in the class is licensed for all of the indications listed above. A summary of current UK licenses for these drugs is shown in Table 1. Please note this is current at the time of print and likely to change as trial data is being released rapidly. It is also important to note while drugs may be licensed, they may not have NICE approval for all indications). Please consult the individual summary of product characteristics (SmPC) or local prescribing information for dosing recommendations and specific indications before prescribing SGLT2 inhibitor therapies.
SGLT2 inhibitors have been shown to reduce the risk of cardiovascular events in people living with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) (Wilding et al, 2022) – including coronary heart disease, acute coronary syndrome, previous myocardial infarction, stable angina, prior coronary or other revascularisation, cerebrovascular disease (ischaemic stroke and transient ischaemic attack) and peripheral arterial disease – alongside their expanded licenses, hence their rise in popularity across national guidance (NICE, 2022a).
Mechanism of action of SGLT2 inhibitors
There are multiple sodium-glucose transporters throughout the body. They are a family of glucose transporters which are integral to glucose reabsorption (Chao and Henry, 2010). The second of these transporters, SGLT2, is found only in the kidneys and, in conjunction with SGLT1, resorbs glucose into the blood from the urine (Chao and Henry, 2010).
As illustrated by Figures 1 and 2, SGLT2 inhibitors act by preventing the reabsorption of glucose and sodium from the SGLT2 transporter in the proximal renal tubule in the kidney. Glucose and sodium are, therefore, lost in urine rather than reabsorbed. This effect results in decreasing the blood glucose level, weight loss, and osmotic diuresis alongside a drop in blood pressure (Dashora et al, 2021).
It is important to note that for each molecule of glucose excreted, a molecule of sodium is excreted.
Who are SGLT2 inhibitors suitable for and when they should be used?
As with any pharmacological therapy, it is important that SGLT2 inhibitor therapy is given to those who are most likely to benefit. It is important to select the right person with diabetes for SGLT2 inhibitor therapy and avoid prescribing it to others who may be at high risk of diabetic ketoacidosis (DKA) – a potential risk of SGLT2 inhibitor therapy that will be discussed in more detail later. The people likely to benefit most are shown in Table 2.
Table 2. People most likely to benefit from SGLT2 inhibitors
| Adults above 18 years with type 2 diabetes and one or more of the following: |
|---|
Established/high risk of atherosclerotic cardiovascular disease (NICE guidance NG28 advises SGLT2 use with proven cardiovascular benefit in people with QRISK2 of 10% or higher):
|
| Chronic kidney disease |
| Heart failure |
| Inadequate glycaemic control with a need to minimise hypoglycaemia |
| Inadequate glycaemic control with a need to minimise weight gain/encourage weight loss |
| People with a clear understanding of the risks associated with SGLT2 inhibitors, how to reduce those risks and the ability to follow sick day rules |
It is important to note some people living with type 2 diabetes might have multiple co-morbidities for which SGLT2 therapy will confer benefit. It is important when prescribing these agents that the primary indication is documented to ensure appropriate monitoring and follow up is in place. For example, this will ensure that someone with heart failure does not end up with diabetes care follow up. Additionally, if the SGLT2 inhibitor will be beneficial for multiple co-morbidities it is good practice that this should also be documented to illustrate the rationale behind the choice of agent and prevent inappropriate switches in therapy.
Who is likely to be at risk with SGLT2 inhibitors?
As with all pharmacological therapy, there are certain patient groups in which SGLT2 inhibitors should be used with caution or avoided. Tables 3 and 4 detail these groups.
Table 3. Situations where SGLT2 inhibitors should be used with caution
| Patient characteristics |
|---|
| Body mass index <25 kg/m2 (<23 kg/m2 in South Asian people) |
| Person adhering to a ketogenic/low calorie/low carbohydrate diet (NICE define this as: 20–50 g/day of carbohydrate or less than 10% of a 2000 kcal/day diet) |
| Recent weight loss |
| Potential for pregnancy |
| People at risk of hypotension or hypovolaemia (eg on diuretic and/or multiple antihypertensive therapies, elderly) |
| Frailty |
| Cognitive impairment or use of medication compliance aid – this may imply inadequate understanding required to follow sick day rules and take action to prevent and identify diabetic ketoacidosis (DKA) |
| Diabetes history |
| Long duration of diabetes (generally over 10 years from diagnosis) |
| Person with very high level of HbA1c >86 mmol/mol |
| Person considered at high risk of acute effects of hyperglycaemia (eg dehydration because of non-adherence to medication) |
| Past history of active foot disease or foot ulceration – consider discussion with specialist, ensure regular preventative footcare |
| Existing diabetic foot ulcers |
| Previous lower limb amputation |
| History of peripheral arterial disease |
| Taking sulphonylureas and/or insulin – increased risk of hypoglycaemia if commenced on SGLT2 |
| Other past medical history |
| On long term or recurrent courses of steroids |
| Raised haematocrit |
| Severe hepatic impairment |
| Recurrent urinary or genital tract infections |
Table 4. Situations where SGLT2 inhibitors should be avoided
| Patient characteristics |
|---|
| Age <18 years |
| Those who are pregnant or breastfeeding, women in their child-bearing years and who are sexually active without contraception |
| Person with excess alcohol consumption or intravenous drug use |
| History of allergic reaction to SGLT2 inhibitor or any of their excipients |
| Diabetes history |
| Suspected or possible type 1 diabetes – unless under specialist advice, noting this is ‘off-label’ use |
| History of diabetic ketoacidosis – unless under specialist advice, noting this is ‘off-label’ use |
| Any diagnosis or suspicion of latent autoimmune diabetes, other genetic causes of diabetes, known pancreatic disease or injury, or people who rapidly progressed to needing insulin within 1 year of diagnosis |
| Current medical history |
| Acutely unwell person (acute medical illness including COVID-19, surgery or planned medical procedure) |
| Active foot disease |
| Inpatient with acute vascular event who is not stable |
| Eating disorder |
| eGFR outside the allowed limits in the up-to-date licensing of the medication being considered |
| Already on SGLT2 inhibitor for other co-morbidity |
| Organ transplant |
| People receiving dialysis |
Potential class side effects
As with any therapy, side effects can affect the disease burden of people taking SGLT2 inhibitors and negatively affect adherence. Clinicians should be aware of the following side effects to properly advise and help people with diabetes manage them accordingly. Common side effects include:
- Increased risk of urinary tract infection (UTI) (this is usually transient and manageable in most people)
- Polydipsia
- Polyuria
- Genito-urinary disorders
- Volume depletion effects (thirst, postural dizziness, hypotension, dehydration)
- Hypoglycaemia (increased risk if on sulphonylureas and/or insulin).
Uncommon but serious side effects that can occur include:
- DKA (Medicines and Healthcare products Regulatory Agency (MHRA), 2016): people should be informed on the signs and symptoms of DKA, and discontinue treatment with the SGLT2 inhibitor immediately if DKA is suspected or diagnosed. It is important to test for raised ketones in people with ketoacidosis symptoms, even if plasma glucose levels are near-normal. Preferably, ketones should be tested by blood rather than urine
- Fournier's gangrene (MHRA, 2019): if suspected, stop the SGLT2 inhibitor and urgently start treatment (including antibiotics and surgical debridement as required). Fournier's gangrene is a rare but potentially life-threatening infection that requires urgent medical attention
- Potential for lower limb amputation: encourage regular preventative foot care (MHRA, 2017). All people taking an SGLT2 inhibitor should be counselled on good preventive foot care. A clinician must review if lower limb complications develop (eg skin ulcer, osteomyelitis or gangrene). Monitor people with risk factors for amputation.
Prescribing, monitoring and reviewing SGLT2 therapy
The value and increased role of SGLT2 therapy in type 2 diabetes are clear, so how does the clinician decide which flozin to chose and what needs to be considered when prescribing?
As mentioned previously, drug licences and dosing (including in renal impairment) vary across the class, so it is vital to check the SGLT2 inhibitor being prescribed is licensed in the person and indication it is intended for, and the dose is correct. Clinicians should consult the individual SmPC or local prescribing information for dosing recommendations and specific indications before prescribing SGLT2 inhibitor therapies.
Given the adverse effects, cautions and contraindications, some considerations when prescribing, monitoring and reviewing people on SGLT2 therapy can reduce the potential risks. Any contact with a person on SGLT2 therapy is a good opportunity to review these points in case of changes in clinical status, lifestyle, medication or other conditions (NICE, 2015).
It is important to minimise the risk of hypoglycaemia by reviewing glucose lowering medications that may cause hypoglycaemia (eg insulin and sulphonylureas) and considering dose reductions of other glucose lowering medication when an SGLT2 inhibitor is initiated, particularly if HbA1c is already at target (Dashora et al, 2021).
The risk of DKA can be minimised by checking if the person may be at increased risk, for example: if they have had a previous episode of DKA, are unwell with intercurrent illness or they are following a very low carbohydrate or ketogenic diet (20–50 g/day of carbohydrate or less than 10% of a 2000 kcal/day diet).
Risk of hypotention can be minimised by reviewing diuretic and anti-hypertensives if hypertension improves or if there is postural hypotension.
It is important to address modifiable risks for DKA before starting an SGLT2 inhibitor. For example, people who are following a very low carbohydrate or ketogenic diet may need to delay treatment until they have changed their diet.
Anything I need to tell my patient?
Before initiating any medical therapy, it is important people are counselled on the new medication, indication and further details. When initiating SGLT2 inhibitors the person should be advised:
- What the benefits of taking SGLT2 inhibitors are to them as an individual
- What side effects may occur and sick day rules and when to stop taking their SGLT2 inhibitor due to associated risks with dehydration and development of DKA
- To seek urgent medical attention if they have symptoms of DKA (eg nausea, vomiting, abdominal pain, stupor, fatigue, difficulty breathing)
- To seek urgent medical attention if symptoms of Fournier's gangrene (eg severe pain, tenderness, erythema, swelling in genital or perineal area)
- About the importance of routine preventative foot care
- To drink plenty of fluids to avoid dehydration unless they have been told to restrict fluids by a healthcare professionals, for example due to heart or kidney problems.
Sick day rules
When a person with diabetes is not well and is unable to eat and drink as normal, some simple rules can prevent further deterioration or DKA. These are commonly referred to as ‘sick day rules’. People with diabetes should be told the following (NICE, 2022a; British National Formulary (BNF), 2022a–d; North of Tyne, 2022; Wilding et al, 2022):
- If ill with diarrhoea, UTI, vomiting, fever or unusual drowsiness, stop SGLT2 inhibitors and do not restart until feeling better and eating/drinking fluids normally
- Restart only after eating normally for at least 24 hours and no longer acutely unwell
- Encourage the person to avoid dehydration with appropriate fluid intake
- Everyone must be counselled on the risk of ketoacidosis and its signs and symptoms (nausea, vomiting, abdominal pain, stupor, fatigue, difficulty breathing) and to stop SGLT2 inhibitor if any symptoms develop
- Seek medical advice if particularly unwell with infection or illness
- To seek urgent medical attention if experiencing symptoms of Fournier's gangrene (eg severe pain, tenderness, erythema, swelling in genital or perineal area)
- Stop SGLT2 inhibitors prior to surgery as advised by pre-op team.
Monitoring requirements
Additional monitoring after starting SGLT2 inhibitors for insufficiently controlled type 2 diabetes is not required (BNF, 2022a–d; North of Tyne, 2022; Wilding et al, 2022). Routine diabetes follow up, including HbA1c and usual annual review processes should continue. Routine monitoring of kidney function should continue as part of routine care, with its frequency guided by national and local guidance for type 2 diabetes, and in line with the person's other co-morbidities as appropriate, but additional routine tests are not required after starting SGLT2 therapy.
The product literature for each of the approved SGLT2 inhibitors advises caution and monitoring of volume status when prescribing alongside diuretics because of the potential for dehydration and hypotension.
It is important to note that it is common to see an initial acute reduction in renal function when an SGLT2 inhibitor is commenced: this is related to the mechanism of action of SGLT2 inhibitors in the renal tubule (Dashora et al, 2021). ABCD/UKKA advise against early testing of kidney function following SGLT2 inhibitor initiation on the basis that withdrawal of the therapy because of an initial decline in eGFR is inappropriate (Dashora et al, 2021). This reduction is usually followed by an overall slowing in the decline of eGFR and long-term reno-protective benefits.
Additional safety information:
- SGLT2 inhibitor treatment should be interrupted in people who are hospitalised for major surgical procedures or acute serious medical illnesses and ketone levels measured, preferably in blood rather than urine. Treatment may be restarted when the ketone values are normal and the person's condition has stabilised (Medicines and Healthcare products Agency (MHRA, 2020).
- The authorisation holder for dapagliflozin has withdrawn the indication for type 1 diabetes mellitus. The removal of the type 1 diabetes indication is not due to any new safety concerns and the other indications of dapagliflozin are unchanged (MHRA, 2021)
Conclusion
In summary, SGLT2 inhibitors are now considered a mainstay of therapy for people with type 2 diabetes. Their mechanism of action confers benefit beyond just glycaemic control, with evidence in heart failure and chronic kidney disease enabling a person-centred approach that is no longer purely glucose centric. As with any medical therapy it is important that agents are started in appropriate cohorts with clear counselling and consideration of the risks. Overall – now it is time to flozinate!
KEY POINTS:
- SGLT2 inhibitors have been shown to reduce the risk of cardiovascular events in people living with type 2 diabetes and atherosclerotic cardiovascular disease
- SGLT2 inhibitors act by preventing the reabsorption of glucose and sodium from the SGLT2 transporter in the proximal renal tubule in the kidney. Glucose and sodium are lost in urine rather than reabsorbed
- It is important to select the right person for SGLT2 inhibitor therapy and avoid in others who may be at high risk of diabetic ketoacidosis
- Before initiating any medical therapy, it is important people are counselled on the new medication, indication and further details
CPD REFLECTIVE PRACTICE:
- Can you explain the mechanism of action of sodium-glucose co-transporter-2 (SGLT2) inhibitors?
- Which of your people with diabetes do you think might benefit from SGLT2 inhibitors? Are you clear on when these should be avoided?
- Are you confident discussing sick day rules with your patients?