New TGA indication for empagliflozin

Empagliflozin’s TGA indication has been extended to include use for reducing cardiovascular death among patients with type 2 diabetes and established cardiovascular disease, but what does this mean for clinical practice?

Here, we discuss the key evidence behind this decision from the EMPA-REG OUTCOME trial – the main findings, limitations of the data, and how relevant these findings are to the Australian context

• Expanded TGA indication for empagliflozin based on recent CV outcome data
  As of January 2017, empagliflozin is also indicated to reduce risk of cardiovascular (CV) death in patients with type 2 diabetes mellitus and established CV disease. This indication is not PBS-subsidised.
• Benefits for CV outcomes demonstrated in EMPA-REG OUTCOME trial
  Over a median follow-up of 3 years, a significant reduction in deaths from CV causes, non-fatal myocardial infarction or non-fatal stroke (10.5% vs 12.15%, HR 0.86, 95% CI 0.79 to 0.99, p = 0.04) was observed in those treated with empagliflozin compared to placebo.
• EMPA-REG cohort consisted of type 2 diabetes patients with established CV disease
  The patients enrolled in this study were at high CV risk, and their CV risk factors were well-treated with BP- and lipid-modifying medicines. It is currently unknown if these results are generalisable to patients at lower CV risk (those without established CV disease).
• Consider side effect profile, renal function and concurrent medicines before prescribing
  Refer to the product information for precautions and contraindications before prescribing empagliflozin. 

Empagliflozin (Jardiance) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor which was TGA-approved in 2014 for the treatment of type 2 diabetes mellitus to improve glycaemic control as an add-on combination therapy with other glucose-lowering medicines.¹ It is also indicated for use as a monotherapy in those who are contraindicated or intolerant to metformin.¹

In January 2017, the TGA indications for empagliflozin were extended to include: ‘in patients with type 2 diabetes mellitus and established cardiovascular disease to reduce the risk of cardiovascular death’.^1-3

This extended indication was based on results reported in the EMPA-REG OUTCOME study,³ following a decision by the United States Federal Drug Administration (FDA) to extend the indication of empagliflozin for this purpose in the United States in December 2016.⁴

On the Pharmaceutical Benefits Scheme (PBS), empagliflozin remains restricted to second- or third-line combination treatment, in patients who have not achieved adequate glycaemic control with metformin and/or a sulfonylurea.⁵ It is subsidised for use in combination with metformin and/or sulfonylurea, or insulin.⁶ 

The EMPA-REG OUTCOME study investigated the impact of empagliflozin on CV morbidity and mortality in patients with type 2 diabetes who have CV disease.⁷

A total of 7,020 patients with established CV disease (prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease) were randomised to receive either empagliflozin (10 or 25 mg) or placebo once daily, in addition to standard of care treatments for type 2 diabetes.⁷ The median observation time was 3.1 years.

The mean age of the cohort was approximately 63 years, 70%–72% were men, mean HbA_1c was approximately 8% and mean BMI was approximately 30.6 kg/m². Within the cohort, 80%–81% were using ACE inhibitors, and 76%–78% were using statins.⁷

Reduced incidence of death from CV causes, non-fatal MI or non-fatal stroke

The primary composite outcome of death from CV causes, non-fatal myocardial infarction, or non-fatal stroke, occurred in a significantly lower proportion of patients taking empagliflozin (pooled) compared to placebo (10.5% vs 12.1%, respectively, hazard ratio (HR) 0.86, 95% CI 0.74 to 0.99, p = 0.04 for superiority).⁷

When expressed as a number needed to treat (NNT), 62 patients would need to be treated with empagliflozin (pooled across 10–25 mg doses) over a 3-year period to prevent death from CV causes, non-fatal myocardial infarction, or non-fatal stroke in 1 patient.

When the individual components of the composite primary outcome were assessed separately, a significantly lower rate of death from CV causes was observed in those treated with empagliflozin (pooled) versus placebo (3.7% vs 5.9%, HR 0.62, 95% CI 0.49 to 0.77). However, no significant difference was found for incidence of non-fatal myocardial infarction (4.5% vs 5.2%, respectively) or non-fatal stroke (3.2% vs 2.6%, respectively) between the empagliflozin and placebo groups, respectively.⁷

There was also no significant difference in the key secondary composite outcome (the primary outcome plus hospitalisation for unstable angina) between the pooled empagliflozin and placebo groups (14.3% vs 12.8%, HR 0.89, 95% CI 0.78 to 1.01, p = 0.08).

Other secondary outcomes measured separately indicated a reduction in deaths from any cause (HR 0.68, 95% CI 0.57 to 0.82, p < 0.001) and hospitalisation for heart failure (HR 0.65, 95% CI 0.50 to 0.85, p < 0.002) in the pooled empagliflozin group compared to placebo.⁷

The mechanism by which empagliflozin may influence CV outcomes has not yet been established.8 It has been speculated that it may involve osmotic diuresis, effects on hyperglycaemia, weight and blood pressure.^7,9,10

Limitations of findings

When considering the expanded indications for empagliflozin based on the EMPA-REG study results in 2016, the Federal Drug Administration Advisory Committee noted a number of issues which require consideration when interpreting the robustness of the primary endpoint results.⁸

Prospective design of the trial was to assess safety, not CV benefit

The FDA noted that the primary objective of the EMPA-REG OUTCOME study was to exclude the possibility that use of empagliflozin to control glycaemia increased CV risk (predominantly absolute CVD risk) by 30% or more compared to the use of alternate, standard of care, glycaemic lowering agents.⁸

It was designed to assess non-inferiority of empagliflozin versus placebo for the 3-point major adverse CV endpoint (CV death, non-fatal MI or non-fatal stroke).¹¹

The primary intent of the EMPA-REG OUTCOME study was not to establish a benefit on a specific outcome, and it was not prospectively designed (eg, sized) with the expressed intent of demonstrating a CV benefit of a glucose-lowering therapy.⁸

Influence of ‘non-assessable’ deaths on primary endpoint

A subset of deaths (n = 124) were categorised as ‘non-assessable’ and adjudicated as presumed CV deaths; this accounted for 71 deaths in the empagliflozin group, and 53 in the placebo group. Those ‘non-assessable’ deaths that were presumed to be CV deaths comprised 40% of CV deaths, and 27% of overall deaths in the trial.⁸

A sensitivity analysis that removed these deaths from the primary composite endpoint (3-point major adverse cardiac events, or MACE) found that empagliflozin was not superior to placebo for reducing death from CV causes, non-fatal MI and non-fatal stroke (HR 0.90, 95% CI 0.77 to 1.06).⁸

Sensitivity analyses on the single component of CV death, excluding the 124 non-assessable deaths, suggested there was a still a reduction in CV deaths (HR 0.59, 95% CI 0.44 to 0.79) and all-cause mortality (HR 0.68, 95% CI 0.57 to 0.82) in those treated with empagliflozin compared to placebo.⁸

The findings reported for safety in the EMPA-REG trial are consistent with the safety profile of empagliflozin.^3,7

While there was no significant difference in the incidence of urinary tract infections between the empagliflozin and placebo groups (18.0% vs 18.1%, respectively), there was a higher incidence of genital infections in patients taking empagliflozin compared to placebo (6.4% vs 1.8%, respectively).⁷

Although concerns have been raised over the renal safety of SGLT2 inhibitors, surprisingly, acute renal failure occurred at a lower rate in the empagliflozin groups compared to placebo (5.2% vs 6.6%, respectively). The percentage of patients with acute renal failure (including acute kidney injury) was lower in the empagliflozin groups than in the placebo group.⁷

Patients in the empagliflozin groups also showed dose-dependent increases in total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides compared to placebo.^8,10 It is unclear whether these effects had any impact on CV outcomes in the trial.⁸

Note that some of the rarer side effects which may emerge with longer term use of empagliflozin in a larger population of people were unlikely to be captured in this trial.

Although the results of the EMPA-REG OUTCOME trial are encouraging, there are limitations to the generalisability of these findings.

The patient population used for the EMPA-REG trial was those with type 2 diabetes who also had established CV disease.⁷ Therefore, these study results apply to a small subset of the Australian population. AIHW data indicates 3%–5% of the Australian population aged ≥ 45 years have both conditions (based on 2011–12 data).¹²

The results of the EMPA-REG trial were also achieved in patients who had well-controlled CV risk factors such as lipids and blood pressure, through treatment with agents such as angiotensin-converting enzyme (ACE) inhibitors, beta blockers, statins and aspirin.⁷ It is unknown whether the benefits demonstrated in this trial will be of the same magnitude in patients with lower CV risk (eg, patients without established CV disease). 

Before prescribing empagliflozin to a patient with type 2 diabetes, consider renal function and concurrent medicines, as well as other factors discussed in the Product Information.

Renal function

For patients with renal impairment, the efficacy of empagliflozin may be reduced.^3,13

Renal function should be assessed before starting treatment and then periodically during treatment (at least annually), and prior to starting concomitant medicines that may reduce renal function.^3,13

Empagliflozin is contraindicated for use in patients with chronic kidney disease stage 4 or 5 (severely impaired renal function including patients receiving dialysis; estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m² or CrCl < 30 mL/min) or if eGFR persistently < 45 mL/min or CrCl persistently < 45 mL/min (CKD stage 3B).³

Increased risk of hypoglycaemia when combined with sulfonylurea or insulin

There may be an increased risk of hypoglycaemia when empagliflozin is taken with a sulfonylurea or insulin.^3,13

When considering addition of empagliflozin to a sulfonylurea or insulin regimen:

• consider using a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycaemia.^3,13
  
• patients should be encouraged to self-monitor their blood glucose on an ongoing basis,⁶ implement appropriate management strategies if their readings fall below 4 mmol/L, and to urgently notify their health professional if this occurs.¹⁴
  

Concurrent medicines

• Avoid use of empagliflozin with loop diuretics.⁶
  
• Empagliflozin has not been studied in combination with glucagon-like peptide 1 (GLP-1) analogues (eg, exenatide, liraglutide).³