SGLT2 inhibitors

• Is a preferred 2nd line agent in cardiovascular disease, especially heart failure, and renal disease as reduces mortality from cardiovascular events and renal disease progression independent of effects on glycaemic control; and leads to weight loss, blood pressure reduction and will not cause hypoglycaemia in or of itself. Therefore, SGLT2 inhibitors (SGLT2i) should be strongly considered in all patients with type 2 diabetes with diabetic renal disease (urinary albumin:creatinine ratio > 3 mg/mmol and/or reduced eGFR) OR heart failure OR known cardiovascular disease OR 5 year CVD risk > 15% regardless of their glycaemic control or other glucose lowering therapies. In these patients, SGLT2i are likely preferable to GLP1RA if heart failure or renal disease predominates, but both classes can be used together with additional benefits on reducing glucose levels, weight and cardiovascular disease. Therefore, SGLT2i is typically the best agent to add to GLP1RA, and GLP1RA to SGLT2i if the HbA1c remains above target. This is a mismatch with the Special Authority criteria as only SGLT2i or GLP1RA will be funded as discussed below.

• To date, there is no convincing evidence that SGLT2i are effective in primary prevention of cardiovascular and/or renal disease. But, in patients with no renal and cardiovascular disease, SGLT2i are a useful 2nd line agent if required for glycaemic control, particularly if weight loss is desirable. Can consider introducing after vildagliptin since vildagliptin in combination with metformin is the only currently known 2nd line agent to delay the need for insulin therapy in type 2 diabetes. But unlike SGLT2i, vildagliptin does not typically lead to weight loss and is usually a less potent glucose lowering therapy. In these patients, GLP1RA will likely lead to greater improvements in glycaemic control and weight loss than SGLT2i, but SGLT2i may be preferable based on co-morbidities and patient preference.

• Reduce glucose levels and circulating volume by inhibiting the sodium glucose co-transporter 2 (SGLT2) in the proximal renal tubule leading to increased urinary excretion of glucose and sodium

• All available SGLT2i in New Zealand are tablets

• Empagliflozin is the only funded SGLT2i in NZ under special authority criteria.

• Special Authority Criteria

• Patient has type 2 diabetes with an HbA1c > 53 mmol/mol despite at least 3 months of regular use of metformin and/or an alternative glucose lowering therapy, not on a funded GLP1RA (i.e. dulaglutide) AND any of the following:
  • Diabetic renal disease  (urinary albumin:creatinine ratio > 3 mg/mmol and/or eGFR < 60 mL/min) OR
  • Known cardiovascular disease (any ischaemic heart disease, cerebrovascular event, peripheral vascular disease, congestive heart failure or familial hypercholesterolaemia) OR
  • 5 year cardiovascular disease risk > 15% OR
  • A high lifetime cardiovascular risk due to onset of diabetes in childhood or as a young adult OR
  • Māori or Pacific ethnicity

• Available in 10 mg and 25 mg tablets or in various empagliflozin/metformin combinations (5 mg/500 mg; 5 mg/1000 mg; 12.5 mg/500 mg; 12.5 mg/1000 mg)

• Typically start at 10 mg daily and can increase to maximum of 25 mg daily after several weeks if no adverse effects AND as required for glycaemic control. NB: The glucose lowering efficacy of SGLT2i is reduced with decreasing renal function and the maximum dose of empagliflozin is 10 mg daily once the eGFR is < 30 mL/min

• Non-funded SGLT2i available in New Zealand includes dapagliflozin 10 mg po daily

• The funding/special authority criteria for SGLT2i in New Zealand ensures access for high risk patients, but is not fully consistent with best practice. Although expensive at approximately $85 per month, all patients with type 2 diabetes who do not meet the special authority criteria should be offered to self-fund SGLT2i if no contraindications or significant precautions in the following situations:
  • Patients with diabetic renal disease and/or heart failure and/or known cardiovascular disease and/or 5 year CVD risk > 15% with an HbA1c < 53 mmol/mol and/or eGFR 60 - 90 mL/min without albuminuria
  • All patients with diabetic renal disease and/or heart failure and/or known cardiovascular disease and/or 5 year CVD risk > 15% on funded GLP1RA (i.e. dulaglutide) therapy
  • Overweight or obese patients with an HbA1c above target despite regular use or inability to tolerate metformin
  • All other patients with an HbA1c above target despite regular use or inability to tolerate metformin and vildagliptin
  • In all patients with an HbA1c to target where a SGLT2i may be preferred to limit adverse effects from either thiazolidinedione, sulfonylurea and/or insulin therapy (particularly weight gain and hypoglyaemia)

• When starting SGLT2i:
  • Provide ongoing support and education for lifestyle management
  • Metformin should be continued unless contraindicated or not tolerated
  • Other glucose lowering therapies should be continued if required for glycaemic control and/or cardiorenal protection (e.g. GLP1RA)
  • If introduced to a regimen with insulin and/or sulfonylureas, then the dose of insulin and/or sulfonylureas may need to be reduced to prevent hypoglycaemia (particularly if the HbA1c is < 64 mmol/mol). Any reduction is best based on blood glucose levels, but recommended proactive reductions in those with tight glycaemic control include a:
    • 15-20% reduction in the dose of total daily insulin. Consider switching premixed insulin or basal plus one insulin regimens to insulin alone if HbA1C < 64 mmol/mol.
    • 50% reduction in the doses of sulfonylureas. Consider stopping sulfonylureas for those on ≤ 80 mg of glicazide per day or ≤ 5 mg of glipizide per day if HbA1c < 64 mmol/mol.
    • NB: Patients with an HbA1c > 75 mmol/mol with no episodes of hypoglycaemia will typically not require any reduction in insulin and/or sulfonylureas
  • Warn of the potential adverse effects and reassure that mild symptoms typically resolve despite continuing treatment. Consider reducing diuretics and antihypertensives if required and discuss importance of remaining well hydrated and sick day management plan (see adverse effects below).

• Adverse effects of SGLT2 inhibitors

• Polyuria – consider reducing diuretics before commencing if applicable

• Genitourinary infections e.g. UTIs, vaginal thrush, balantitis

• Patients should be educated on correct hygiene and warned of the rare risk of Fournier’s gangrene that is a medical emergency

Fournier's gangrene is a type of necrotising fasciitis involving the external genitalia, perineal or perianal areas and may be life threatening. Although the vast majority of genitourinary infections associated with SGLT2 inhibitors are mild, consider acute referral to secondary care if significant pain, fevers and redness out of keeping with mild infection

• Hypotension – consider reducing antihypertensive agents before commencing/increasing dose

• Increases risk of diabetic ketoacidosis (DKA) including normoglycaemic DKA but still rare (1 in 3000)

• NB: Patients and health professionals need to be aware of the risk of DKA with SGLT2i (including with normal glucose levels)

• Need to stop SGLT2i in acute illness or at least 3 days (including day of) before any major elective procedure or any elective procedure that involves reduced oral intake for > 12 hours (including dental surgery). Also need to stop SGLT2i at least 3 days before any bowel prep (e.g. colonoscopy) or a low carbohydrate diet (e.g. bariatric surgery) pre-procedure. The SGLT2i should not be restarted until the patient is well and eating and drinking normally as per their sick day management plan. For more information please see NZSSD/ADS alert
• Patients should informed to present to their GP practice or hospital if experiencing symptoms of nausea, vomiting or abdominal pain to have their ketones checked
• Capillary ketones > 1.5 mmol/L on SGLT2i require urgent medical attention
• Cautious use of SGLT2i in type 2 diabetes is recommended for those high risk for DKA

• Risk factors for DKA in type 2 diabetes

• Previous DKA
• Insulin deficiency with low carbohydrate diet (e.g < 130 g of carbohydrate per day) and/or significant alcohol use

• SGLT2i are not recommended for use in:

• Children < 10 years, pregnancy and breastfeeding
• eGFR < 20 mL/min*
  • *NB: International guidelines (e.g. KDIGO) now recommend that all SGLT2i including empagliflozin can be started safely when the eGFR is > 20 mL/min and only need to be stopped if adverse effects occur of if the patient starts dialysis.
• Previous severe genitourinary infections
• Those on ketogenic diets (due to increased risk of DKA )
• Type 1 diabetes, diabetes due to loss of pancreatic function, or previous DKA without specialist approval

Risk factors for DKA in type 2 diabetes

• Previous DKA
• Insulin deficiency with low carbohydrate diet (e.g < 130 g of carbohydrate per day) and/or significant alcohol use