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Home | Articles | Renal | Sodium Glucose Transporter 2 Inhibitors (SGLT2i)

Sodium Glucose Transporter 2 Inhibitors (SGLT2i)

Last updated 1st March 2022

Summary Chart

Background

  1. Significant improvement in cardiovascular and renal outcomes have been demonstrated with SGLT2 inhibitors in clinical trials(1-3)
  2. MHRA have approved use of canagliflozin for in adults with T2DM as add-on to standard of care for treatment of diabetic kidney disease
  3. Dapagliflozin has been approved by MHRA for treatment of non-diabetic chronic kidney disease (CKD) and/or heart failure, in patients without diabetes as well as patients with diabetes and has been shown to improve renal and cardiovascular outcomes(4,6).

Chronic Kidney Disease Indication – Patients Without Diabetes

  1. Dapagliflozin can be prescribed to treat kidney disease to reduce the risk of kidney failure.
  2. Dapagliflozin also reduces cardiovascular mortality and heart failure complications.
  3. It can be commenced where eGFR > 15ml/min and it can be continued until KRT is required.
  4. Note that the DAPA-CKD trial mostly recruited patients with eGFR > 25ml/min and ACR > 20mg/mmol (comparable PCR > 50mg/mmol).

Chronic Kidney Disease Indication – Patients With Diabetes

  1. Canagliflozin can be prescribed to treat diabetic kidney disease to reduce risk of kidney failure (dialysis or need for kidney transplant) in type 2 diabetes.
  2. Canagliflozin 100mg can be commenced when eGFR 30ml/min and there is albuminuria (ACR > 30mg/mmol or PCR > S0mg/mmol); it can be continued until kidney replacement treatment (KRT) is required.
  3. Dapagliflozin can also be prescribed in patients with diabetes to reduce the risk of kidney failure similar to its use in people without diabetes
  4. Any of the SGLT2i can be prescribed for HbAlc lowering, so long as the eGFR thresholds for each medication are followed.

General Indications

  1. Across SGLT2 trials, efficacy was similar across a range of renal function, and there was benefit even in patients with low starting eGFR.

Contraindications

  1. In general, SGLT2i should be avoided in type 1 diabetes and in those who have a history of DKA.
  2. These patients were excluded from the SGLT2i trials.
  3. SGLT2i are contraindicated in APKD and have not been tested in patients with SLE or vasculitis. SGLT2i have not been extensively tested in kidney transplant patients with some reports on their use for glycaemic control(6).

Renal Function

Initiation

  1. Canagliflozin can be initiated with eGFR above 30ml/min in patients with albuminuria (ACR > 30mg/mmol or PCR > S0mg/mmol) to reduce renal risk in type 2 diabetes.
  2. Dapagliflozin can be initiated with eGFR above 15ml/min.

Discontinuation

  1. Canagliflozin & dapagliflozin can be continued until need for kidney replacement therapy (KFRT, dialysis or transplant)

HbA1c

  1. In the CREDENCE trial, there was minimal lowering of HbAlc by canagliflozin at the prescribed dose of 100mg.
  2. Nevertheless, HbAlc should be monitored in patients with diabetes after commencement of SGLT2 inhibitors.
  3. Where HbAlc control is already tight, relaxing of other glycaemic medications should be considered.
  4. Where HbAlc is very high, better glycaemic control should be achieved prior to starting SGLT2.
  5. Patients should be encouraged to attend primary or secondary care services for management of diabetes.
  6. At eGFR <30ml/min is unlikely that these drugs have a major hypoglycaemic effect.

General Safety Advice

  1. A small drop in GFR (<30%) may occur within first 4-6 weeks of commencement. This should stabilise and is similar to that seen with ACE inhibitors.
  2. There is no evidence that eGFR measurement at an interval after initiation can identify patients who are intolerant and we do not recommend routine blood checks specifically to assess effect on GFR at this time point.
  3. Patients should undergo eGFR measurement at intervals based on their eGFR and at least annually.
  4. SGLT2i are potassium neutral.
  5. SGLT2i should be used with caution in the frail elderly due to the risk of intravascular volume depletion.
  6. SGLT2i are contraindicated in pregnancy and breast feeding.
  7. We suggest that is reasonable to check kidney function at 3-4 months after starting an SGLT2i in patients with eGFR <45ml/min.

Sick Day Guidance

  1. Sick day guidance should be given when introducing these agents, with the aim of reiterating the advice when able.
  2. Provision of written advice regarding sick day rules is available. This is due to increased risk of ketosis and is different to ‘sick day’ rules for other drugs e.g. ACE inhibitors.
  3. For patients on insulin treatment, additionally they should always be advised never to stop their insulin as part of the sick day response.
  4. SGLT2i should also be stopped for elective surgical procedures which involve fasting including day case procedures, or in patients fasting for religious reasons.

Diabetic Ketoacidosis

  1. The risk of diabetic ketoacidosis (DKA) is elevated, including euglycaemic DKA.
  2. There is a mechanistic association with glycosuria and ketogenesis and this can be exacerbated during periods of physiological stress.
  3. The risk of this complication is small, particularly if good sick day guidance is provided.
  4. SGLT2i should be avoided in type 1 diabetes, and where there is diagnostic doubt regarding the ‘type’ of diabetes, due to enhanced risk of DKA.
  5. There should be caution where:
    • People who have rapidly progressed to requiring insulin (within one year of diagnosis)
    • Past history of DKA
    • History of pancreatic disease – including alcoholic pancreatitis as a cause of their diabetes

Dehydration

  1. In people on significant diuretic doses (furosemide >40mg) consider reducing the dose as the SGLT2i will induce diuresis.

Urinary Tract Infection

  1. SGLT2i are associated with an increased risk of fungal UTI in women, and serious genitourinary infection in men.
  2. These agents should be used in caution in patients with a relevant history.
  3. Vigilance regarding personal hygiene should be encouraged.
  4. Give advice on the need to seek medical attention (via GP, pharmacy or urgent care centre) should they develop symptoms of a genital infection.

Peripheral Vascular Disease

  1. In the CANVAS programme, there was an increased incidence of amputation in patients receiving canagliflozin, although this was not replicated in the CREDENCE or DAPA-CKD studies.
  2. We suggest avoiding these drugs in patients with ischaemic foot disease.

References

  1. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. Wanner et al, NEJM 2016
  2. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. Neal et al, NEJM 2017
  3. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. Perkovic, NEJM 2019
  4. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. McMurray, NEJM 2019
  5. Dapagliflozin in patients with chronic kidney disease. Heerspink, NEJM 2020
  6. Sodium-Glucose Cotransporter 2 Inhibitors and Kidney Transplantation: What Are We Waiting For? Patel, Kidney 360 2021
  7. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1) Dandona, Lancet Diabetes & Endocrinology 2017

Links

  1. SGLT2i Glasgow Guideline [pdf]
  2. NHSD&G Sick Day Rules Card (A6) [pdf]
  3. UK Kidney Association Clinical Practice Guideline [pdf]

Reproduced with the kind permission of the authors; Keith Gillis, Emily McQuarrie, Patrick Mark, NHS Greater Glasgow & Clyde SGLT2i Guideline 3.0 260821. NHSD&G Contacts Dr Michael Kelly, Dr Muna Mohamed & Dr Fiona Green.