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Overview

This Guidelines summary provides practical and pragmatic clinical guidance for primary care on the use of sodium–glucose co-transporter-2 (SGLT-2) inhibitors in the context of chronic kidney disease (CKD) in adults. The recommendations aim to:

  • provide guidance on the use of SGLT-2 inhibitors in people with CKD, focusing on the potential to modify risk of kidney disease progression
  • support safe implementation of SGLT-2 inhibitors into clinical practice in people with CKD.

The guideline provides four types of recommendation, covering:

  • use (who should be offered SGLT-2 inhibition?)
  • implementation (how should SGLT-2 inhibition be used?)
  • research (what are areas of ongoing clinical uncertainty?)
  • audit (can you demonstrate effective implementation?).

For a complete set of recommendations, including clinical research recommendations, refer to the full guideline.

View this summary online at www.guidelines.co.uk/456676.article

SGLT-2 inhibition and renal protection in people with CKD in the context of type 2 diabetes mellitus

Recommendations for use

  • In people with type 2 diabetes mellitus and an estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73 m or greater, the UK Kidney Association (UKKA) recommends initiating sodium–glucose co-transporter-2 (SGLT-2) inhibition[A] in those with:
    • a urine albumin:creatinine ratio (uACR) of 25 mg/mmol or greater, attributed to diabetic nephropathy
    • established coronary disease or stable symptomatic heart failure (irrespective of ejection fraction)
  • The UKKA recommends initiating SGLT-2 inhibition in those with type 2 diabetes mellitus and a uACR of 25 mg/mmol or greater, attributable to a nondiabetic cause[B]
  • The UKKA suggests initiating SGLT-2 inhibition to modify cardiovascular risk in those with type 2 diabetes mellitus, an eGFR of 25–60 ml/min/1.73 m2, and a uACR of less than 25 mg/mmol, recognising that effects on glycaemic control will be limited.

Recommendations for implementation

  • The UKKA recommends using SGLT-2 inhibitors with demonstrated efficacy for their given indications[A]
  • The UKKA recommends using clinically appropriate single-agent renin–angiotensin system (RAS) blockade in combination with SGLT-2 inhibition wherever RAS blockade is indicated and tolerated
  • The UKKA suggests following NICE guidelines on screening for albuminuria:[C] a single uACR of 70 mg/mmol or greater, or a confirmed measurement of 25–69 mg/mmol fulfil recommendations for use of SGLT-2 inhibition based on albuminuria
  • The UKKA suggests using uACR to assess for sufficient proteinuria to guide SGLT-2 inhibitor use—reagent strips and protein:creatinine ratio should generally not be used;[C]  more pragmatic approaches to identifying risk of kidney disease progression may be necessary while local access to uACR measurement is improved
  • The UKKA suggests that, when used to slow kidney disease progression or heart failure risk, SGLT-2 inhibition can be continued until the need for dialysis or kidney transplantation arises
  • The UKKA suggests that co-prescription of SGLT-2 inhibition with a mineralocorticoid receptor antagonist can be considered, where each are individually indicated
  • The UKKA suggests that the beneficial effects of SGLT-2 inhibition on renal outcomes in people with type 2 diabetes mellitus are likely to be a class effect, but there is insufficient data in people without diabetes mellitus to be conclusive
  • The UKKA suggests the beneficial effects of SGLT-2 inhibition on heart failure are likely to be a class effect, irrespective of the presence or absence of diabetes mellitus.

Audit measures

  • The UKKA proposes the following audit measures, focusing on those guidelines supported by robust randomised evidence:
    • the proportion of people with each grade-1 recommendation for use prescribed an SGLT-2 inhibitor (with exploration of reasons for non-use to direct quality improvement projects)
    • the proportion of people prescribed an SGLT-2 inhibitor not on concomitant RAS blockade.

SGLT-2 inhibition and renal protection in people with CKD without diabetes mellitus

Recommendations for use

  • In people without type 2 diabetes mellitus and with an eGFR of 25 ml/min/1.73 m2  or greater:
    • the UKKA recommends initiating SGLT-2 inhibition[A] in those with stable symptomatic heart failure (irrespective of ejection fraction)
    • the UKKA recommends initiating SGLT-2 inhibition[A] in those with a uACR of 25 mg/mmol or greater, excluding people with polycystic kidney disease or on immunological therapy for renal disease.[B,D]

Recommendations for implementation

See the section, SGLT-2 inhibition and renal protection in people with CKD in the context of type 2 diabetes mellitus, which includes recommendations for implementation irrespective of diabetes mellitus status.

Audit measures

See the section, SGLT-2 inhibition and renal protection in people with CKD in the context of type 2 diabetes mellitus, which provides audit measures irrespective of diabetes mellitus status.

Selection of SGLT-2 inhibitors

Table 1: Dosing of SGLT-2 inhibitors based on current UK regulatory licenses

  • All doses are once daily.
CKD=chronic kidney disease; DKD=diabetic kidney disease; DM=diabetes mellitus; eGFR=estimated glomerular filtration rate; HFrEF=heart failure reduced ejection fraction; SGLT-2=sodium–glucose co-transporter-2; uACR=urinary albumin:creatinine ratio

✓=initiate

—=continuation, not for initiation

X=discontinue

[A] Initiate if for treatment of DKD and uACR > 30mg/mmol

[B] Continue if initiated for albuminuria

[C] In patients with diabetes mellitus, the glucose-lowering efficacy of dapagliflozin is reduced when eGFR is <45 ml/min/1.73 m2, and is likely absent in patients with severe renal impairment. Therefore, if eGFR falls below 45 ml/min/1.73 m2, additional glucose-lowering treatment should be considered in patients with diabetes mellitus

 SGLT-2 inhibitor eGFR, ml/min/1.73 m2        
 >90  60–90  45–60  30–45  15–30  <15
Canagliflozin (type 2 DM)   ✓ 100–300 mg  ✓ 100–300 mg  ✓ 100 mg  ✓ 100 mg[A]  — 100 mg[B]  — 100 mg[B]
 Dapagliflozin (type 2 DM)
 ✓ 10 mg  ✓ 10 mg  ✓ 10 mg[C]  ✓ 10 mg[C]  ✓ 10 mg[C]  X
 Dapagliflozin (CKD)  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  X
 Dapagliflozin (HFrEF)  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  X
 Empagliflozin (type 2 DM)  ✓ 10–25 mg  ✓ 10–25 mg  — 10 mg  X  X  X
 Empagliflozin (HFrEF)  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  ✓ 10 mg  X
 Ertugliflozin  ✓ 5–15 mg  ✓ 5–15 mg  — 5–15 mg  X  X  X

Current licensed indications for SGLT-2 inhibitor use

Canagliflozin (Invokana)

  • Canagliflozin is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
    • as monotherapy when metformin is considered inappropriate due to intolerance or contraindications
    • in addition to other medicinal products for the treatment of diabetes

      For this indication, initiation can be at either the 100 mg or 300 mg dose at an eGFR of greater than 60 ml/min/1.73 m2, but once the eGFR has dropped below 60 ml/min/1.73 m2, the dose should be reduced to the 100 mg dose, and the treatment stopped if the eGFR drops below 45 ml/min/1.73 m2
  • For treatment of diabetic kidney disease as an add-on to standard of care (for example, angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers)

    Initiation can occur down to an eGFR of 30 ml/min/1.73 m2 if uACR is greater than 30 mg/mmol, and can be continued if started for this indication down to the need to commence dialysis or renal transplantation.

Dapagliflozin (Forxiga)

  • Dapagliflozin is indicated in adults for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
    • as monotherapy when metformin is considered inappropriate due to intolerance
    • in addition to other medicinal products for the treatment of type 2 diabetes mellitus

      For this indication, dapagliflozin can be initiated at a dose of 10 mg. In patients with diabetes mellitus, the glucose lowering efficacy of dapagliflozin is reduced when eGFR is less than 45 ml/min/1.73 m2, and is likely absent in patients with severe renal impairment. Therefore, if eGFR falls below 45 ml/min/1.73 m2, additional glucose lowering treatment should be considered in patients with diabetes mellitus
  • Dapagliflozin is indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction
  • It is not recommended to initiate treatment with dapagliflozin in patients with an eGFR less than 15 ml/min/1.73 m2. Dapagliflozin is indicated in adults for the treatment of CKD.

Empagliflozin (Jardiance)

  • Empagliflozin is indicated in adults for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
    • as monotherapy when metformin is considered inappropriate due to intolerance
    • in addition to other medicinal products for the treatment of diabetes

      When used for treatment of insufficiently controlled type 2 diabetes mellitus, empagliflozin can be initiated at a dose of either 10 or 25 mg a day above an eGFR of 60 ml/min/1.73 m2. If the eGFR drops between 45 and 60 ml/min/1.73 m2, then the dose needs to be reduced to 10 mg a day, and the treatment stopped when the eGFR drops below 45 ml/min/1.73 m2
  • Empagliflozin is indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction

    For treatment of heart failure in patients with or without type 2 diabetes mellitus, empagliflozin 10 mg may be initiated or continued down to an eGFR of 20 ml/min/1.73 m2.

 Ertugliflozin (Steglatro)

  • Ertugliflozin is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
    • as monotherapy in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications
    • in addition to other medicinal products for the treatment of diabetes

      Currently, ertugliflozin can be initiated at a dose of either 5 or 15 mg a day above an eGFR of 60 ml/min/1.73 m2. Ertugliflozin should not be initiated at an eGFR of less than 60 ml/min/1.73 m2, but if already established on treatment, it may be continued down to an eGFR of 45 ml/min/1.73 m2. Treatment should be stopped when the eGFR drops below 45 ml/min/1.73 m2.

Prescribing SGLT-2 inhibitors safely

Diabetic ketoacidosis

Recommendations for implementation

  • The UKKA recommends that people with type 1 diabetes mellitus should only have SGLT-2 inhibitors initiated under the strict direction of the diabetes team (see the section, Use in special populations of specific interest)
  • The UKKA recommends that people with type 2 diabetes mellitus at greater risk of diabetic ketoacidosis (DKA; defined in Table 5a.1 of the full guideline) should have SGLT-2 inhibitors initiated with caution after discussion with the diabetes team
  • The UKKA recommends that SGLT-2 inhibitors are discontinued when a patient develops DKA
  • The UKKA suggests that, after an episode of DKA and where a clear contributing factor has been identified, there should be discussion with the person and clinical team to establish whether the benefits of re-introducing an SGLT-2 inhibitor outweigh the risks
  • When initiating SGLT-2 inhibitors, the UKKA suggests that individuals should be advised on the signs and symptoms of DKA, and be instructed to temporarily withhold SGLT-2 inhibitors and to seek immediate medical advice if symptoms develop
  • The UKKA recommends always offering advice on sick day guidance when initiating SGLT-2 inhibitors, and reminding patients of this at every medication review
  • The UKKA suggests that individuals taking SGLT-2 inhibitors should be advised against following a ketogenic diet
  • The UKKA suggests that for people who choose to intermittently fast (for example, for Ramadan), and particularly for those who are elderly, are on diuretics, or have chronic kidney disease, consider withholding SGLT-2 inhibitors for the duration of the fasting period, and for those people with diabetes, ketone testing should be undertaken if unwell.

Audit measures

  • The proportion of people with CKD on SGLT-2 inhibitors with evidence of provision of sick day guidance
  • The proportion of people with CKD in whom SGLT-2 inhibitors were withheld during acute illness, and the proportion appropriately reinitiated on recovery.

Hypoglycaemia

Recommendations for implementation

  • The UKKA recommends considering reducing the dose of insulin/sulfonylureas (SUs)/meglitinides when initiating SGLT-2 inhibitors to reduce the risk of hypoglycaemia
  • The UKKA recommends that, when initiating SGLT-2 inhibitors in people taking SUs (for example, gliclazide) or meglitinides (for example, repaglinide) when glycated haemoglobin (HbA1c) is less than 58 mmol/mol and eGFR is greater than 45 ml/min/1.73 m2, consider reducing the dose of the SU or meglitinide by 50% to reduce risk of hypoglycaemia
  • The UKKA recommends that, when starting SGLT-2 inhibitors in people taking insulin when HbA1c is less than 58 mmol/mol and eGFR is greater than 45 ml/min/1.73 m2, consider reducing the insulin dose by 20% to avoid hypoglycaemia
  • The UKKA recommends that, when starting SGLT-2 inhibitors in people taking only metformin ± pioglitazone ± dipeptidyl peptidase-4 inhibitor/gliptin or glucagon-like peptide-1 receptor agonist therapy, no dosage adjustment is necessary.

Audit measures

  • The proportion of people on insulin/SUs with an HbA1c  less than 58 mmol/mol and an eGFR greater than 45 ml/min/1.73 m2, whose therapy was appropriately reduced when initiating SGLT-2 inhibitors.

Acute kidney injury, hypovolaemia, and potassium

  • The UKKA recommends that individuals initiated on an SGLT-2 inhibitor do not routinely require an early assessment of renal function or potassium following initiation of treatment
  • The UKKA suggests that, if an individual has a renal function assessment within the first few weeks after initiation of an SGLT-2 inhibitor, a decline in eGFR needs to be interpreted with caution and in the context of an expected drug effect to avoid unwarranted discontinuation of treatment
  • The UKKA suggests that individuals on diuretics are counselled on the symptoms of hypovolaemia, and advised to seek medical attention if they develop any such symptoms after starting SGLT-2 inhibition
  • The UKKA suggests that clinicians consider an early clinical review and, if appropriate, a diuretic or antihypertensive dose reduction in individuals they consider at high risk of hypovolaemia
  • The UKKA recommends that SGLT-2 inhibitors are temporarily withheld during acute illness.

Peripheral vascular disease and amputation risk

Recommendations for implementation

  • The UKKA suggests avoiding initiation of SGLT-2 inhibitors in the presence of active foot disease (infection, ulceration, and ischaemia), and withholding treatment in those who develop foot complications while taking an SGLT-2 inhibitor
  • The UKKA suggests a shared decision-making approach, with appropriate counselling on the risks and benefits of treatment and the importance of routine preventative foot care measures, for:
    • individuals at high risk of amputation (previous amputations, existing peripheral vascular disease, peripheral neuropathy)
    • reinitiation of SGLT-2 inhibitors after treatment and full resolution of a foot complication that occurred while taking SGLT-2 inhibitors.

Fracture risk

Recommendations for implementation

  • In people with CKD treated with SGLT-2 inhibitors, the UKKA suggests that monitoring of bone parameters, including calcium, phosphate, and parathyroid hormone, should be performed as appropriate for CKD stage.[C]

Multimorbidity and frailty

Recommendations for implementation

  • The UKKA suggests an approach to care that takes account of frailty and multimorbidity where these apply; this can include:
    • establishing the person’s goals, values, and priorities
    • consideration of the balance of disease and treatment burden (for example, prognostic benefits in people with limited life expectancy or frailty)
    • agreeing an individualised management plan.

Mycotic genital infections and Fournier’s gangrene

Recommendations for implementation

  • The UKKA recommends that all people are counselled on the risks of mycotic genital infections prior to initiation of SGLT-2 inhibitors
  • The UKKA recommends that all people are counselled on self-care to maintain good genital hygiene
  • The UKKA recommends that all people are counselled on the symptoms of mycotic genital infections, and how to seek help including self-management
  • The UKKA suggests that, for those individuals with a history of recurrent mycotic genital infections on SGLT-2 inhibition, consideration is given to offering prophylactic antifungal treatment, which should be reviewed after 6 months of therapy or earlier if clinically indicated
  • The UKKA suggests that SGLT-2 inhibitor therapy can be continued during the treatment of mycotic genital infections
  • The UKKA highlights the specific Medicines and Healthcare products Regulatory Agency warning, and suggests that all people are counselled on the symptoms of Fournier’s gangrene, and advised to stop SGLT-2 inhibitors and to seek urgent help if they develop such symptoms.

Urinary tract infections

Recommendations for implementation

  • The UKKA recommends temporary discontinuation of SGLT-2 inhibitors when treating pyelonephritis or urosepsis (see section 5a.1.2 of the full guideline).

Children, pregnancy, and breastfeeding

Recommendations for implementation

  • The UKKA suggests that SGLT-2 inhibitors are not used in children under 18 years of age
  • The UKKA suggests that all women of childbearing potential are counselled, prior to conception, on the risks of SGLT-2 inhibitors during pregnancy
  • The UKKA suggests that SGLT-2 inhibitor therapy is discontinued upon planning, suspicion, or confirmation of pregnancy
  • The UKKA suggests that SGLT-2 inhibitors are not used in women who are breastfeeding.

Use in special populations of specific interest

Type 1 diabetes mellitus

Recommendations for implementation

  • The UKKA recommends that SGLT-2 inhibitors only be initiated in people with type 1 diabetes mellitus under the strict direction of the diabetes team
  • The UKKA suggests considering referring people with type 1 diabetes mellitus to the specialist diabetes team for consideration of an SGLT-2 inhibitor if they have an eGFR of 25 ml/min/1.73 m2  or greater and a uACR of 25 mg/mmol or greater, attributable to diabetic nephropathy, despite being on maximum tolerated angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker
  • The UKKA recommends that all people with type 1 diabetes mellitus started on SGLT-2 inhibitors be provided with ketone monitoring, and be advised on the signs and symptoms of DKA and to seek immediate medical advice if any of these symptoms develop or ketone levels are greater than 0.6 mmol/l.

Kidney transplant recipients

Summary statements

  • There is currently insufficient evidence on safety and efficacy to provide recommendations for the use of SGLT-2 inhibition in people with a functioning kidney transplant
  • Any use of SGLT-2 inhibition to treat diabetes mellitus in a kidney transplant recipient should be evaluated by multidisciplinary discussion
  • Note: effects on glycaemic control at an eGFR of less than 60 ml/min/1.73 m2 in people with a kidney transplant appear small, and the potential risk of complications from urinary tract infection should be considered.

Heart failure with preserved ejection fraction and acute decompensated heart failure (irrespective of ejection fraction)

  • There is currently insufficient evidence to provide further recommendations for use of SGLT-2 inhibition in people with CKD with acutely decompensated heart failure
  • See sections 2 and 3 of the full guideline for recommendations for use in other forms of heart failure or to modify cardiovascular risk.

Footnotes

[A] See the section, Prescribing SGLT-2 inhibitors safely, for a summary of indications/licensed uses.

[B] DAPA–CKD provides the key clinical evidence and excluded people with a kidney transplant, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and those receiving immunological therapy for renal disease in the past 6 months.

[C] NICE. Chronic kidney disease: assessment and management. NICE Guideline 203. NICE, 2021. Available at: nice.org.uk/ng203.

[D] Randomisation into a trial may also be appripriate to address clinical uncertainty (see section 2.3 of the full guideline, which includes recommendations for research irrespective of diabetes mellitus status).

 

Full guideline:

UK Kidney Association. UK Kidney Association clinical practice guideline: sodium-glucose co-transporter-2 (SGLT-2) inhibition in adults with kidney disease. Bristol: UKKA, 2021. Available at: ukkidney.org/sites/renal.org/files/UKKA guideline_SGLT2i in adults with kidney disease v1 18.10.21.pdf

Published date: 18 October 2021.

Credit:

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