SGLT-2 Inhibitors – Beyond Diabetes

Dapagliflozin and empagliflozin are sodium-glucose co-transporter 2 (SGLT-2) inhibitors. These medications inhibit SGLT-2 in the renal proximal convoluted tubules.

The SGLT-2 protein is responsible for the resorption of around 90% of the glucose from the glomerular filtrate. This makes SGLT-2 an attractive target for diabetes therapies as inhibition of SGLT-2 increases the amount of glucose removed by the kidneys. As the name suggests, SGLT-2 also transports sodium. Therefore, SGLT-2 inhibitors also increase the amount of sodium that is removed via the kidneys. This produces natriuresis and a mild diuresis that is associated with a moderate and sustained reduction in blood pressure.

Significant improvements in glycaemic control can be achieved with SGLT-2 inhibitors, and these medications were originally only indicated for the management of type 2 diabetes. However, studies have demonstrated cardiorenal protective effects and SGLT-2 inhibitors now also have a place in the management of heart failure and chronic kidney disease (CKD).

Indications

The current approved indications for SGLT-2 inhibitors in Australia are:

• Dapagliflozin
  • Type 2 diabetes – glycaemic control
  • Type 2 diabetes – reduce risk of hospitalisation for heart failure in patients with established cardiovascular disease or risk factors for cardiovascular disease
  • Heart failure – as an adjunct to standard therapy
  • Chronic kidney disease – to reduce the risk of disease progression in patients with proteinuric CKD.
• Empagliflozin
  • Type 2 diabetes – glycaemic control
  • Type 2 diabetes – prevention of cardiovascular death in patients with established cardiovascular disease
  • Heart failure – as an adjunct to standard therapy
  • Chronic kidney disease – to reduce the risk of disease progression.

Studies have demonstrated that the cardiorenal benefits become evident soon after randomisation. The mechanisms responsible for these benefits are not fully understood. However, these effects appear to be independent of glucose lowering and are apparent in patients with and without diabetes.

Some mechanisms that have been suggested include:

• Modulation of the renin-angiotensin-aldosterone (RAAS) system
• Osmotic diuresis and natriuresis to reduce preload;
• Vascular effects, such as improved endothelial function, to reduce afterload;
• Inhibition or reversal of adverse cardiac remodelling; and
• Improved myocardial metabolism to improve cardiac efficiency.

Evidence

Cardiovascular outcomes

The EMPA-REG OUTCOME trial evaluated cardiovascular outcomes of empagliflozin in patients with type 2 diabetes and high cardiovascular risk. Over 7,000 patients were randomised to receive empagliflozin or placebo. The empagliflozin group demonstrated significantly lower rates of death from cardiovascular causes (3.7% vs. 5.9%), hospitalisation for heart failure (2.7% vs 4.1%), and death from any cause (5.7% vs 8.3%).

Similar findings were reported for dapagliflozin in the DECLARE-TIMI trial. This was a larger study with more than 17,000 patients with type 2 diabetes at risk of atherosclerotic cardiovascular disease. Patients randomised to the dapagliflozin group had a lower rate of hospitalisation for heart failure compared to placebo (2.5% vs 3.3%).

The cardiovascular benefits of these studies prompted their investigation in people without diabetes. Studies such as the DAPA-HF and EMPEROR-Reduced trials demonstrated that SGLT-2 inhibitors may provide cardiovascular benefits for patients with heart failure regardless of their diabetes status.

Renal outcomes

In the initial cardiovascular outcomes trial, EMPA-REG OUTCOME, patients in the empagliflozin group were significantly less likely to experience a rapid decline in renal function over a median exposure period of 2.6 years. The potential renal benefits of SGLT-2 inhibitors were further investigated in the following trials:

• CREDENCE
  • Drug – canagliflozin (no longer available in Australia)
  • Population – type 2 diabetes and kidney disease
  • Outcome – 32% lower relative risk of end-stage kidney disease
• DAPA-CKD
  • Drug – dapagliflozin
  • Population – patients with CKD
  • Outcome – hazard ratio for the primary outcome (composite of sustained decline in the eGFR of ≥ 50%, end-stage kidney disease, or death from renal causes) was 0.56 (95% CI: 0.45 to 0.68).
• EMPA-KIDNEY trials
  • Drug – empagliflozin
  • Population – patients with CKD
  • Outcome – hazard ratio for the progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 mL/min/1.73 m², a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) was 0.71 (95% CI: 0.62 to 0.81).

A recently published umbrella review of network meta-analyses provided further support for the use of SGLT-2 inhibitors in CKD. This study compared the safety and efficacy of SGLT-2 inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) in patients with CKD. The authors concluded that all three classes of medication are associated with significant reductions in the risk of major cardiovascular events and the progression of CKD compared to placebo. Furthermore, indirect evidence suggests that SGLT-2 inhibitors may be the most attractive option when considering efficacy together with safety.

Adverse effects

As SGLT-2 inhibitors increase the amount of glucose in the urine, they are associated with an increased risk of genital infections (e.g. vulvovaginal candidiasis, balanitis). Other common adverse effects include polyuria, dysuria, thirst, and constipation. Hypoglycaemia can occur, particularly when used in combination with a sulfonylurea or insulin.

Serum creatinine may rise initially (potentially related to volume depletion). This is sometimes referred to as the “GFR dip”. This acute reduction in eGFR is reversible and typically followed by a partial recovery. The slower decline in eGFR compared to placebo then becomes apparent.

Ketoacidosis

Ketoacidosis has been rarely associated with the use of SGLT-2 inhibitors. A large cohort study from Canada and the United Kingdom found that SGLT-2 inhibitors significantly increased the risk of diabetic ketoacidosis (DKA) compared to dipeptidyl peptidase 4 (DPP-4) inhibitors. The hazard ratio was 1.86 for dapagliflozin and 2.52 for empagliflozin.

Diabetic ketoacidosis can occur in the setting of carbohydrate deficit. Under these conditions, serum insulin levels are low, and the body reduces the use of glucose and increases the use of fat as an energy source. Increased lipolysis, increased free fatty acid generation, and ketoacidosis can occur.

Hyperglycaemia is a classic component of DKA diagnosis. However, in patients taking SGLT-2 inhibitors, blood glucose levels can be normal or mildly elevated. This unusual presentation has been associated with delays in diagnosis.

There are many potential risk factors for the development of this adverse event. This includes acute illness or infection, surgery or trauma, dehydration, low carbohydrate intake, and alcohol abuse. Hospitalised patients are at greater risk as predisposing factors are more common in this population. To reduce the risk, SGLT-2 inhibitors should be avoided in patients on low carbohydrate diets and should be withheld during acute illness and prior to elective procedures.

The recommendation to withhold SGLT-2 inhibitors prior to elective surgery is directed towards patients with diabetes. There is currently a lack of evidence to guide recommendations for patients without diabetes who are taking an SGLT-2 inhibitor. While the risk of ketoacidosis in this group is thought to be significantly lower, the Council of Australian Therapeutic Advisory Groups currently recommends that the guidelines for patients with diabetes can also be followed for patients without diabetes. If the SGLT-2 inhibitor is withheld for surgery, it can be restarted once the patient is eating and drinking normally and kidney function has returned to baseline.

While SGLT-2 inhibitors have shown some promise as an adjunct therapy in type 1 diabetes, they are currently not recommended to be used in this population. This is due to an increased risk of DKA.

Recommendations

Heart failure

The Therapeutic Guidelines recommend dapagliflozin or empagliflozin for patients with heart failure, unless contraindicated. This should be used in addition to standard care (i.e. a renin-angiotensin system inhibitor, beta blocker and mineralocorticoid receptor antagonist for patients with heart failure with reduced ejection fraction).

Chronic kidney disease

The Chronic Kidney Disease (CKD) Management in Primary Care handbook recommends the use of an SGLT-2 inhibitor for patients with CKD and proteinuria (with or without diabetes) to reduce the risk of progressive decline in kidney function. The handbook advises against initiating an SGLT-2 inhibitor in patients with an eGFR <25mL/min/1.73m².