Leeds – Local Clinical Pathways

Leeds Citywide Guideline for the Safe and Appropriate Use of SGLT2 inhibitors

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  This pathway is adapted from Leeds Citywide Guideline for the Safe and Appropriate Use of SGLT2 inhibitors ^{Link will activate when authors share document on public facing website}
- What are SGLT2 inhibitors?
  
  SGLT2 inhibitors are an established class of medications for the treatment of type 2 diabetes, heart failure and chronic kidney disease which act by preventing the absorption of glucose and sodium, mainly from the proximal renal tubule in the kidney.
  
  Glucose and sodium are, therefore, lost in urine. People do not become hyponatraemic (unless on diuretics as well) as most of the sodium is reabsorbed in the distal tubule.
  
  Licences for the SGLT2 inhibitors medications are changing rapidly.
  Always check the up-to-date licences. The information in this guidance was correct at the time of publication.
- What are the benefits of SGLT2 inhibitors?
  
  Clinical trials using SGLT2 inhibitors have provided strong evidence in the trial populations for reduced risk of major cardiovascular, renal and heart failure events.
  There are many benefits to these agents to people living with diabetes:
  - weight loss, up to 3kg of body weight can be seen.
  - blood pressure reductions of 3-5mmHg seen in the systolic blood pressure.
  - improvements in blood glucose with reductions in HbA1c of up to 10mmol/mol (1.0%) in people with good renal function (there is limited efficacy in people with an eGFR < 45ml/min/1.73m².)
  If the person is not on medications that put you at risk of hypoglycaemia already (insulin, sulphonylureas or meglitinides) there is minimal risk of hypoglycaemia.

Which SGLT2 inhibitors do I use?

SGLT2 inhibitors have licences for treatment of insufficiently treated type 2 diabetes, chronic kidney disease (CKD) (with and without type 2 diabetes) and symptomatic chronic heart failure (HF) with reduced ejection fraction (with or without type 2 diabetes). SGLT2 inhibitors have also been shown to reduce the risk of cardiovascular events in people living with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) i.e., previous MI, previous stroke, and peripheral arterial disease

One significant co-morbidity
Diabetes		Heart Failure		CKD
Dapagliflozin or Empagliflozin		Dapagliflozin or Empagliflozin		Dapagliflozin
Two significant co-morbidities
	Diabetes	Heart Failure	<b>With albuminuria:</b> urine ACR ≥ 22.6mg/mmol and eGFR 25-75ml/min/1.73m<sup>2</sup> <br>- either attributed to diabetic and non-diabetic causes in someone living with diabetes <br>- or in someone not living with diabetes excluding those with polycystic kidney disease or someone on immunological therapy for renal disease	<b>With urine ACR < 22.6mg/mmol</b> and eGFR 25-75ml/min/1.73m<sup>2</sup>	ASCVD is not a licenced indication and trial evidence for benefits in ASCVD in combination with other licenced indications have led to the choices in this guidance
Diabetes		Dapagliflozin or Empagliflozin	Dapagliflozin	Dapagliflozin	Empagliflozin
Heart Failure	Dapagliflozin or Empagliflozin		Dapagliflozin	Dapagliflozin or Empagliflozin	Empagliflozin
<b>With albuminuria:</b> urine ACR ≥ 22.6mg/mmol and eGFR 25-75ml/min/1.73m<sup>2</sup> <br>- either attributed to diabetic and non-diabetic causes in someone living with diabetes <br>- or in someone not living with diabetes excluding those with polycystic kidney disease or someone on immunological therapy for renal disease	Dapagliflozin	Dapagliflozin			Dapagliflozin
<b>With urine ACR < 22.6mg/mmol</b> and eGFR 25-75ml/min/1.73m<sup>2</sup>	Dapagliflozin	Dapagliflozin or Empagliflozin
ASCVD is not a licenced indication and trial evidence for benefits in ASCVD in combination with other licenced indications have led to the choices in this guidance	Empagliflozin	Empagliflozin	Dapagliflozin
Three or more significant co-morbidities (Diabetes and/or ASCVD and/or HF and/or CKD*)
Dapagliflozin
We would not advocate switching between SGLT2 inhibitors if co-morbidity changes. The above suggestions for initial therapy are based on licences and clinical trial data.

Looking to Start an SGLT2 inhibitor

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Discuss individualised benefits of taking an SGLT2 inhibitor and document the indication at initiation.
⇓
Check that this is the right drug for the person

- ⇓
  Caution in all in the following situations:
  - People diagnosed with or at risk of frailty – these drugs can be efficacious for those at high cardiovascular or renal risk, particularly those with heart failure, they also have a low hypoglycaemia risk when used alone or with agents that don’t cause hypoglycaemia. You should however think about implications of weight loss and risks of candidiasis, increased urinary incontinence, increased risks of euglycemic diabetic ketoacidosis and risks with fluid depletion
  - Those on loop diuretics (risk of hypotension and dehydration esp. in the elderly)
  In addition to the above caution in people living with diabetes in the following situations:
  - Person adhering to a ketogenic diet, recent weight loss or people intermittently fasting (more important if elderly or CKD or on diuretics) e.g., during Ramadan, should consider withholding medication or introducing ketone testing
  - People on steroid therapy (either IV or oral)
  - Body mass index under 25 kg/m² (under 23kg/m² in south Asian people)
  - Person considered at high risk of acute effects of hyperglycaemia (e.g., dehydration may be caused due to non-adherence to other medications which will be an additive risk for those on SGLT2 inhibitor therapy)
  - Person with very high HbA1c >86mmol/mol (~10% in old HbA1c)
  - Cognitive impairment as it may interfere with the adequate understanding to take action to prevent and identify Diabetic ketoacidosis (DKA)
  ⇓
- ⇓
  Avoid in all in the following situations:
  - eGFR lower than allowed in the up-to-date licensing of the medication being considered
  - Person with excess alcohol consumption or IVDU
  - Unwell person, inpatient or otherwise (e.g.acute medical illness including sepsis, COVID-19, acute vascular event and still unstable, dehydration, surgery or planned medical procedure)
  - Pregnancy or breast feeding (females of child-bearing potential should be counselled on risks in pregnancy and to withhold the medication if they are planning pregnancy)
  - Eating disorder - unless specialist diabetes team are happy for the person to be initiated on or to continue on therapy (seek specialist advice)
  - Age < 18 years
  - Active foot disease (infection, ulceration, or ischaemia) unless the specialist team have advised to continue or have reinitiated
  - Organ transplant
  In addition to the above avoid in people living with diabetes in the following situations:
  - History of diabetic ketoacidosis unless a clear cause was identified, and the specialist teams involved believe that benefit outweighs risk of continued care
  - Type 1 diabetes unless specifically indicated by specialist team (NB: now off licence use)
  - Any diagnosis or suspicion of diabetes due to other causes, including T1D, a latent autoimmune diabetes (LADA), other genetic causes of diabetes, known pancreatic disease or injury, or people who rapidly progressed to needing insulin within 1 year of diagnosis
  ⇓
- If a person is suitable to start the SGLT2 inhibitor then discuss with them the risks and benefits of the medications so that they are able to make an informed decision about their care.
  Document your discussions, particularly around informing people of the risks and then document the persons decision about their treatment :
  
  Discuss the most common side effects:
  
  Genital mycotic infections
  
  advise people this is common in both male and females. Provide genital hygiene advice and advice on how to self-treat. Most initial cases can be treated with topical antifungals and won’t recur. The SGLT2 inhibitor can be continued during treatment. Consider reviewing therapy or prophylactic antifungal therapy if recurrent infections.
  
  Increased urination
  
  advise people to expect increased frequency and/or increased volume of urine
  
  Volume depletion side effects
  
  discuss with people the signs (thirst, postural dizziness, hypotension and dehydration) and advise people that you will take particular care in someone who is frail/elderly. Discuss measuring blood pressure in lying and standing positions in those at risk of falls and those on diuretics
  
  Discuss rare side effects:
  
  Diabetic ketoacidosis (can be euglycemic)
  
  advise people that this is a rare side effect in people living with diabetes but that it can be serious if it does occur: Inform and advise people living with diabetes about how to prevent, recognise and how to get treatment for <div> <p style="margin-bottom: 8px; text-align: center;"><b><u>BOX 1: Diabetic Ketoacidosis (DKA)</u></b></p> <p style="margin-bottom: 8px;">Explain that DKA is an uncommon and serious side effect caused by the build-up of ketones which are being produced due to insulin deficiency (absolute or relative). Inform people of the common causes as part of a preventative strategy:</p> <ol> <li>Acute Illness/infections</li> <li>Starvation/fasting</li> <li>Carbohydrate deficient diet i.e., ketogenic diets (50-130g of carbohydrate per day)</li> <li>Excessive exercise</li> <li>Alcohol</li> <li>Surgery</li> <li>Illicit drugs</li> <li>Reduced insulin dose (if on insulin)</li> <li>Dehydration</li> </ol> <p style="margin-bottom: 8px;">With SGLT2 inhibitors DKA may occur with normal glucose levels.</p> <p style="margin-bottom: 8px;">Be aware and make your patient aware of the signs and symptoms of DKA: Nausea, vomiting, abdomen pain, stupor, fatigue, and difficulty breathing.</p> <p style="margin-bottom: 8px;">Ketones need to be tested urgently if DKA is suspected. DO NOT Use urine ketone testing. Test capillary ketones if you have access to a ketone meter and if not refer to the hospital for blood ketone testing. If ketones > 1.5mmol/L then further tests may be needed to ascertain if the person has a DKA.</p> </div>
  
  Amputation:
  
  advise people that this is an uncommon side effect. In people living with diabetes, it would be advisable to encourage routine preventative foot care and ask all people taking SGLT2 inhibitors to report any wounds, discolouration, or tender/painful feet. If they discover any foot problems, they should seek medical attention immediately and therapy should be withheld if significant foot problems arise (such as infection or skin ulcers or ischaemia). Advise people that evidence for this comes only from the CANVAS trial (involving Canagliflozin) and not other SGLT2 inhibitors. High risk people should receive standard education on relevant diabetes foot care.
  
  Fournier’s Gangrene
  
  advise people this is a very rare side effect. People should remain alert to any perianal discomfort (pain or swelling) that is moderate to severe and may be accompanied by general malaise. Advise on good genital hygiene and how to seek help if they do develop symptoms.
  
  Fracture Risk
  
  advise people this is rare however in some cases it may be important to monitor bone parameters e.g., in people with CKD calcium, phosphate and PTH would be monitored. Advise people that evidence for this comes only from trial data involving Canagliflozin.
  
  Discuss with people the importance of remaining well hydrated unless they are advised to restrict fluids.
  Discuss <div> <p style="margin-bottom: 8px; text-align: center;"><b><u>BOX 2: Sick Day Rules</u></b></p> <p style="margin-bottom: 8px;">To be used when a person with diabetes is not well and unable to eat and drink as normal</p> <ol> <li>If ill with diarrhoea, vomiting or fever stop the SGLT2 inhibitor and do not restart until eating/drinking fluids normally.</li> <li>When people with diabetes who take insulin are not able to eat, it might be possible for them to consume milk, fruit juice, yoghurt or soup in place of meals and adjustments may need to be made to usual medication regimens e.g., insulin.</li> <li>Drink plenty of water/sugar free fluids to avoid dehydration for up to 24 hours. If not resolved > 24 hours seek medical advice.</li> <li>Seek medical advice if seriously unwell with infection or illness.</li> </ol> </div> and other times when <div> <p style="margin-bottom: 8px; text-align: center;"><b><u>BOX 3: When to stop SGLT2 inhibitors</u></b></p> <p style="margin-bottom: 8px;">When there is an increased risk of DKA:</p> <ol type="a"> <li>Acute medical illness, including for COVID-19 infection</li> <li>Admission for elective surgery or procedure requiring starvation</li> <li>Vomiting and/or diarrhoea</li> <li>Dehydration</li> </ol> <p style="margin-bottom: 8px;">Restart only AFTER the patient has been eating and drinking normally for 24 hours AND no longer acutely unwell. You may need to commence alternative treatments in the interim.</p> </div>
- Before you prescribe, a few checks.
  
  In people living with diabetes review medications that may cause hypoglycaemia, such as insulin, meglitinides and sulphonylureas. If someone is below or at their individualised blood glucose or HbA1c targets, or there is other cause for concern (e.g., high in day variability of blood glucose) consideration should be given to reduce doses when the SGLT2 inhibitor is started (a 50% reduction in dose of meglitinide or sulphonylurea or a 20% dose reduction in insulin may be appropriate). If the insulin requirement reduces considerably, one should be cautious of a higher risk of developing Diabetic Ketoacidosis (DKA). The healthcare professional should review diuretic and anti-hypertensive therapy periodically if hypertension improves or if there is postural hypotension. Before initiating, review licences for renal function (NB no additional renal function monitoring should be required for SGLT2 inhibitors above standard monitoring dictated by care plan):
- Licences for the SGLT2 inhibitors medications are changing rapidly. Always check the up-to-date licences:
  Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin
  The information in this guidance was correct at the time of publication (Feb 2022).
- <div> <p style="margin-bottom: 8px; text-align: center;"><b><u>Useful Resources for people living with diabetes</u></b></p> <p style="margin-bottom: 8px;">TREND leaflets (free to register) <a href="https://trenddiabetes.online/resources/" target="_blank">https://trenddiabetes.online/resources/</a></p> <ul> <li>Diabetes and your Kidneys</li> <li>How to reduce your risk of genital fungal infection</li> <li>Type 2 DKA</li> <li>Type 2 Diabetes: what to do when you are ill</li> </ul> <div> <div class="pill-nav2" style="text-align:center;"> <a href="https://e7fvz575be6.exactdn.com/wp-content/uploads/pdf/dotn024ae8fb1b78500b7bc752b98e9b6d92.pdf" target="_blank">SADMAN Sick Day mnemonic</a> <a href="https://abcd.care/sites/abcd.care/files/site_uploads/Images/ABCD_A4_Leaflet_Final%20%28002%29.jpg" target="_blank">ABCD SGLT2 information</a> </div> <p></p> </div> </div> || <div> <p style="margin-bottom: 8px; text-align: center;"><b><u>References</u></b></p> <p style="margin-bottom: 8px;">Dashora U, Gregory R, Winocour P, Dhatariya K, Rowles S, Macklin A, Rayman G, Nagi D, Whitehead K, Beba H, De P, Patel DC; ABCD executive committee and Diabetes UK. Association of British Clinical Diabetologists (ABCD) and Diabetes UK joint position statement and recommendations for non-diabetes specialists on the use of sodium glucose co-transporter 2 inhibitors in people with type 2 diabetes (January 2021). Clin Med (Lond). 2021 May;21(3):204-210. doi: 10.7861/clinmed.2021-0045. PMID: 34001571; PMCID: PMC8140708.</p> </div>
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