SGLT2 inhibitors for diabetic kidney disease

Whilst initially devised as a treatment to improve glycaemic control in diabetes, significant improvement in cardiovascular and renal outcomes have been demonstrated with SGLT2 inhibitors in the cardiovascular outcome trials (1-3) and MHRA/EMA have approved a additional licence for canagliflozin for In adults with T2DM as add-on to standard of care for treatment of diabetic kidney disease, and it is likely that similar license changed may occur for other drugs in this class, based on further clinical trials where SGLT2i are associated with improved renal and cardiovascular outcomes and survival, even in the absence of diabetes (4,6).

This is a rapidly evolving area where new clinical trial data are emerging frequently, and drug licensing and guidelines are frequently altered. Clinicians should refer to up to date sources of information for contemporary guidance about drug indications (5, 7).

Recently, canagliflozin received a license extension to allow prescription for reduction in renal and cardiovascular risk in patients with type 2 diabetes and albuminuria, in addition to the existing licensed indication of reduction of HbA1C in type 2 diabetes.

Canagliflozin can be prescribed to treat diabetic kidney disease in order to reduce risk of progressive renal impairment (dialysis or need for kidney transplant). The eGFR thresholds should be referred to, and the indication is predicated on the presence of albuminuria (ACR > 30mg/mmol or PCR > 50mg/mmol).

It is likely that the licensing indications for other drugs within the class will broaden and clinicians are advised to refer to contemporary guidance. Empagliflozin and dapagliflozin have also been shown to reduce the risk of kidney failure and improve cardiovascular outcomes in patients with type 2 diabetes in clinical trials but their current prescribing license does not reflect their effect on renal outcomes.

Initiation

• Canagliflozin can be initiated with eGFR above 30ml/min in patients with albuminuria (ACR >
  30mg/mmol or PCR > 50mg/mmol) to reduce renal risk
  
  

Discontinuation

• Canagliflozin can be continued until end stage kidney disease (ESKD) the licenses for Dapagliflozin and Empagliflozin state that they should be stopped at eGFR below 45ml/min. It should be noted that both drugs have been extensively used in clinical trials in patients with GFRs down to 30ml/min (and dapagliflozin is licenced for initiation in patients with heart failure without GFR restriction)

In the CREDENCE trial, there was minimal lowering of HbA1c by canagliflozin at the prescribed dose of 100mg. Nevertheless, HbA1c should be monitored in the patient group in which SGLT2 inhibitors are prescribed. Where HbA1c control is already tight, relaxing of other glycaemic medications should be considered. Where HbA1c is very high, better glycaemic control should be achieved prior to starting SGLT2. Patients should be encouraged to attend primary or secondary care services for management of diabetes.

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. 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. Patients should undergo eGFR measurement at intervals based on their eGFR and at least annually. SGLT2 are potassium neutral. SGLT2i should be used with caution in the frail elderly due to the risk of intravascular volume depletion. SGLT2i are contraindicated in pregnancy and breast feeding.

Sick day guidance

Sick day guidance should be given when introducing these agents, with the aim of reiterating the advice when able. 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. For patients on insulin treatment, additionally they should always be advised never to stop their
insulin as part of the sick day response.

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

The risk of diabetic ketoacidosis (DKA) is elevated, including euglycaemic DKA. There is a mechanistic association with glycosuria and ketogenesis and this can be exacerbated during periods of physiological stress. The risk of this complication is small, particularly if good sick day guidance is provided.

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.

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
• Testing of C-peptide can helpful although this requires interpretation, but caution should be
  advised in people with very low levels of this peptide.

Dehydration

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

Urinary tract infection

SGLT2i are associated with an increased risk of fungal UTI in women, and serious genitourinary infection in men. These agents should be used in caution in patients with a relevant history. Vigilance regarding personal hygiene should be encouraged.
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

In the CANVAS programme, there was an increased incidence of amputation in patients receiving canagliflozin, although this was not replicated in the CREDENCE study. A warning remains in the medicines compendium: “Before initiating Invokana, consider factors in the patient history that may increase the risk for amputation. As precautionary measures, consideration should be given to carefully monitoring patients with a higher risk for amputation events and counselling patients about the importance of routine preventative foot care and maintaining adequate hydration. Consideration may also be given to stopping treatment with Invokana in patients who develop events which may precede amputation such as lower-extremity skin ulcer, infection, osteomyelitis or gangrene”.

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. SIGN 154: https://www.sign.ac.uk/our-guidelines/pharmacological-management-of-glycaemic-
   control-in-people-with-type-2-diabetes/
6. Dapagliflozin in patients with chronic kidney disease. Heerspink, NEJM 2020
7. Home - electronic medicines compendium (emc)

	Canagliflozin	Dapagliflozin	Empagliflozin
Indication(s)	T2DM with albuminuria (ACR >30mg/mmol) for reduction of renal and CV risk irrespective of glycaemia to reduce renal risk AND/OR Reduction of HbA1c in T2DM as monotherapy when metformin not tolerated or as add-on.	Reduction of HbA1c in T2DM asmonotherapy when metformin not tolerated or as add-onAND/ORTreatment of symptomatic chronic heart failure with reduced ejection fraction.	Reduction of HbA1c in T2DM as monotherapy when metformin not tolerated or as add-on.
Starting dose	100mg once daily	10mg once daily	10mg and 25mg once daily
eGFR at commencement	>30ml/min	>60ml/min(expect when indicated for heart failure then no restriction)	>60ml/min
eGFR at discontinuation	ESKD	<45ml/min(expect when indicated for heart failure then ESKD)	<45ml/min