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Abstract
The prevalence of type 2 diabetes is rising, and in 2015 more than 5% of adults in the UK were affected by this condition.1,2 Management of type 2 diabetes includes encouraging lifestyle changes (increased exercise, modification of diet and smoking cessation) alongside the provision of medication to minimise long-term complications and manage blood sugar control while avoiding unwanted effects of drug treatment.3 Of particular importance, people with type 2 diabetes are at increased risk of cardiovascular disease, and therefore the aims of treatment also include modification of associated risk factors.2-5
▼ Empagliflozin (Jardiance-Boehringer Ingelheim) is the third sodium-glucose co-transporter-2 (SGLT2) inhibitor licensed for use in the UK. It was launched in August 2014, and acts in a similar way to the other SGLT2 inhibitors, ▼ dapagliflozin and ▼ canagliflozin, by inhibiting renal glucose resorption and promoting glycosuria.6 It is indicated for the treatment of type 2 diabetes in adults to improve glycaemic control, as monotherapy when metformin cannot be used, and in combination with other glucose-lowering drugs including insulin. Here we review the evidence for empagliflozin and discuss the results of a recent study that assessed cardiovascular outcomes.
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Background
Although a range of drugs are licensed to manage glycaemic control in type 2 diabetes, evidence of improved cardiovascular outcomes for these treatments is limited.7 Metformin has been shown to reduce macrovascular and microvascular complications compared to diet control alone in a trial that included 753 overweight patients with newly diagnosed type 2 diabetes.8 In comparison, the UK Prospective Diabetes Study (UKPDS) 33 trial demonstrated that sulfonylureas reduced micro- but not macrovascular complications.9,10
The European Medicines Agency (EMA) requires evidence that any new drug for glycaemic control does not increase the risk of cardiovascular complications.11 Placebo-controlled randomised trials of newer agents (e.g. dipeptidyl peptidase 4 [DPP-4] inhibitors and glucagon-like peptide 1 receptor agonists) have not shown that they improve cardiovascular outcomes.12-14
SGLT2 inhibitors
In healthy adults, the kidney filters approximately 180g of glucose per day,15 almost all of which is resorbed via sodium-glucose co-transporter (SGLT) proteins.16 SGLT2, found in the initial segment of the proximal convoluted tubule, is responsible for 90% of this resorption, with SGLT1, found in the distal aspect of the proximal tubule, accounting for the remaining 10%. Inhibitors of SGLT2 reduce renal glucose resorption by competitive inhibition of SGLT2, thereby increasing urinary glucose excretion.17 In addition to reducing plasma glucose levels, this increase in urinary glucose excretion results in a loss of 200–300kcal per day, which may contribute to modest weight reduction. A moderate fall in systolic blood pressure, attributable to mild osmotic diuresis, may also occur.17 The mechanism of action of SGLT2 inhibitors is independent of insulin and therefore may result in a lower risk of hypoglycaemia.18 The efficacy of SGLT2 inhibitors is dependent on the functional status of the kidney,19 with treatment effects diminishing with decreasing renal function.18
Empagliflozin
The starting dose for empagliflozin is 10mg daily and it can be taken with or without food (maximum dose 25mg daily).6 After administration, empagliflozin is rapidly absorbed with maximal concentration achieved after 1.5 hours. It has an elimination half-life of 12.4 hours and is eliminated in the faeces (41%) and urine (54%). Empagliflozin does not inhibit or induce any cytochrome p450 isozymes and pharmacokinetic interaction studies did not demonstrate any drug-drug interactions of clinical significance.6,18
Clinical trial evidence
Four phase III double-blind placebo-controlled studies were included in the clinical trial programme.20-23 The main inclusion and exclusion criteria were similar for all four trials. Adults with type 2 diabetes with glycated haemoglobin (HbA1ci) ≥ 7.0% and < 10.0%, and a body mass index (BMI) ≤ 45kg/m2 were included. Exclusion criteria included history of acute coronary syndrome, stroke or transient ischaemic attack within 3 months prior to study entry and estimated glomerular filtration rate (eGFR) < 30mL/min/1.73m2 (< 50mL/min/1.73m2 for the monotherapy trial).20 At 24 weeks, empagliflozin produced statistically significant reductions in HbA1c compared with placebo (primary outcome). Across the studies, the difference from placebo in the absolute reduction of HbA1c from baseline ranged from –0.48% to –0.74% for empagliflozin 10mg and –0.59% to –0.85% for empagliflozin 25mg. In addition, patients treated with empagliflozin had statistically significant reductions in weight (secondary outcome) compared with placebo (1.8–2.2kg).20-23
Similarly designed placebo-controlled trials compared empagliflozin 25mg as add-on to basal daily insulin, with or without metformin and/or a sulfonylurea,24 and add-on to multiple daily insulin with or without metformin.25 The difference from placebo in change from baseline HbA1c was –0.7% and –0.5% at 18 weeks, for empagliflozin for the basal daily insulin and multiple daily insulin trials, respectively (p< 0.001 for both).24,25 Empagliflozin (25mg daily) was compared to glimepiride (maximum 4mg daily) in a randomised double-blind non-inferiority trial as add-on therapy for patients inadequately controlled on metformin.26 At 2 years, empagliflozin resulted in a statistically significant reduction in HbA1C (–0.66% vs. –0.55%; absolute difference –0.11%, 95% CI –0.19 to –0.02). Body weight was also reduced with empagliflozin (–3.1kg vs. + 1.3kg; absolute difference 4.5kg). In addition, there were fewer hypoglycaemic events (plasma glucose ≤ 3.9mmol/L) with empagliflozin (2% vs. 24%; p< 0.0001).
Other data
The reductions in HbA1c demonstrated with empagliflozin are broadly similar to those seen with the other SGLT2 agents, canagliflozin and dapagliflozin.17,19 A systematic review of published randomised controlled trials of SGLT2 inhibitors compared HbA1c reduction via a network meta-analysis and found minimal difference between agents.27
Cardiovascular outcomes and mortality trial
The effect of empagliflozin on cardiovascular outcomes was investigated in the EMPA-REG OUTCOME study.28 In this double-blind trial, 7,028 people with type 2 diabetes and a history of cardiovascular disease (myocardial infarction, stroke or unstable angina, or evidence of significant coronary artery or occlusive peripheral artery disease)29 were randomised to take empagliflozin 10mg, 25mg or placebo daily.28 Other inclusion criteria included BMI ≤ 45kg/m2, eGFR ≥ 30mL/min/1.73m2,ii and HbA1c of ≥ 7.0% and ≤ 10.0% on stable doses of glucose-lowering therapy, or HbA1c of ≥ 7.0% but ≤ 9.0% if not on glucose-lowering therapy. The primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. The key secondary outcome was the composite of the primary outcome plus hospitalisation for unstable angina. The study was designed as a non-inferiority trial, with the non-inferiority margin for the hazard ratio (HR) for the pooled empagliflozin groups versus placebo set at 1.3. (This is the margin stipulated in the USA Food and Drug Administration guidance for studies investigating cardiovascular risk in new treatments for type 2 diabetes).30 Background glucose lowering therapy was unchanged for the first 12 weeks after trial entry, though rescue therapy was permitted if the patient had a fasting plasma glucose > 13.3mmol/L. After week 12, glucose-lowering therapy was adjusted to achieve glycaemic control. Cardiovascular risk factors were also treated throughout the trial according to the best available local standard of care.
The median duration of treatment and observation time was 2.6 and 3.1 years, respectively. The primary outcome occurred in 10.5% of patients in the empagliflozin group compared with 12.1% in the placebo group (HR 0.86, 95.02% CI 0.74 to 0.99, p< 0.001 for non-inferiority; p= 0.04 for superiority) with the benefits appearing during the first few months of treatment. The key secondary outcome occurred in 12.8% with empagliflozin and 14.3% with placebo (HR 0.89, 95% CI 0.78 to 1.01, p< 0.001 for non-inferiority; not significant for superiority). Several other prespecified outcomes were also statistically significant, including cardiovascular death (3.7% vs. 5.9%; HR 0.62, 95% CI 0.49 to 0.77), hospitalisation for heart failure (2.7% vs. 4.1%; HR 0.65, 95% CI 0.50 to 0.85) and death from any cause (5.7% vs. 8.3%; HR 0.68, 95% CI 0.57 to 0.82). The differences in the occurrence of myocardial infarction (4.8% vs. 5.4%) or stroke (3.5% vs. 3.0%) were not statistically significant.
The reduction in the primary composite outcome corresponds to a number-needed-to-treat (NNT) of 63 patients for 2.6 years to prevent one event. The NNT for death from any cause was 39.
Limitations of the study
Patients had established cardiovascular disease and a very high baseline risk of an event. Small relative differences would therefore be easier to detect in such a high-risk population. Nevertheless, the primary outcome only just reached statistical significance. Secondary analysis of the outcomes from the individual doses of empagliflozin compared with placebo were not statistically significant. In a prespecified subgroup of patients with higher baseline HbA1c (≥ 8.5%), the difference in the primary outcome was not statistically significant.
The improvements in cardiovascular outcomes appear to be partly related to a reduction in heart failure-related risk and are thought to have occurred too rapidly to be as a result of a reduction in atherosclerotic disease.31 Empagliflozin was associated with a slight reduction in blood pressure, which may explain some of the cardiovascular outcome benefit. More patients in the placebo group received additional antihypertensive medication compared with the empagliflozin group (47.4% vs. 40.6%).29
Cardiovascular outcome trials are also underway for the other SGLT2 inhibitors, the results of which might help establish whether the improved outcomes reported in the empagliflozin study are a class effect.
Safety
Pooled data from the pivotal trials showed similar rates of adverse effects with empagliflozin 10mg, 25mg and placebo (71.8%, 70.1% and 74.1% respectively).18 There was an increased risk of genital infections (e.g. vulvovaginitis, balanitis) with empagliflozin 10mg and 25mg (4.4% and 4.7%) compared with placebo (1.1%); more common in women than in men. The frequency of urinary tract infections with empagliflozin was similar to placebo. Although there was no significant increase in hypoglycaemic events in most trials, there was an increased incidence compared to placebo when empagliflozin was used in combination with a sulfonylurea.18 The incidence of adverse effects caused by volume depletion (e.g. hypotension, syncope) was higher in patients receiving diuretics (2.5%, 2.7% and 2.2% for empagliflozin 10mg, 25mg and placebo, respectively).18
Recent safety alerts from the Medicines and Healthcare products Regulatory Agency (MHRA) and the EMA have highlighted that rare but serious and sometimes fatal cases of diabetic ketoacidosis (DKA) have been reported with SGLT2 inhibitors.32,33 Patients taking these drugs should be warned about the symptoms of DKA. Many reports were of atypical DKA with only moderately increased blood glucose levels. DKA should be considered in patients presenting with non-specific symptoms (e.g. vomiting, anorexia, excessive thirst) and where suspected, SGLT2 inhibitors should be discontinued and only restarted after resolution of symptoms if another clear precipitating factor is resolved.33 Patients admitted for severe acute illness and for major surgery should have SGLT2 inhibitors withheld until their condition has stabilised.
Cautions and contraindications
As the mechanism of action of empagliflozin is dependent on renal function, the drug should not be started in patients with eGFR < 60mL/min/1.73m2.6 For patients who are taking empagliflozin, in whom eGFR is persistently below 60mL/min/1.73m2, the dose should be reduced or maintained at 10mg daily. If eGFR falls persistently below 45mL/min/1.73m2 empagliflozin should be discontinued. Although dose adjustment in hepatic impairment is not required, empagliflozin should not be used in severe hepatic impairment due to limited experience. As SGLT2 inhibition can cause volume depletion, caution should be used if initiating in patients 75 years and over, those with a history of hypotension and those on diuretics. In conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status and electrolytes is recommended and temporary interruption of treatment should be considered until the fluid loss is corrected.6 Initiation in patients over 85 years is not recommended.
Cost
The cost of treatment with empagliflozin (10–25mg/day) is £36.59 for 28 days.
National guidance
The National Institute for Health and Care Excellence (NICE) recommended empagliflozin as an option for type 2 diabetes:34
as add-on to metformin if a sulfonylurea is contraindicated, not tolerated or there is a significant risk of hypoglycaemia or its consequences
as part of triple therapy with metformin and a sulfonylurea or metformin and a thiazolidinedione (pioglitazone)
in combination with insulin with or without other antidiabetic drugs.
A separate NICE appraisal reviewed SGLT2 inhibitors as monotherapy.35 NICE recommended canagliflozin, dapagliflozin or empagliflozin as an option for monotherapy for type 2 diabetes when metformin is contraindicated or not tolerated only if:
a DPP-4 inhibitor would otherwise be prescribed, and
a sulfonylurea or pioglitazone is not appropriate.
The Scottish Medicines Consortium (SMC) recommended empagliflozin for type 2 diabetes as dual therapy with metformin, as triple therapy with metformin plus standard of care, or added to insulin therapy plus standard of care.36 SMC advice on the use of empagliflozin as monotherapy has been superseded by NICE's appraisal guidance on the use of SGLT2 inhibitors as monotherapy.36
Conclusion
▼ Empagliflozin is the third sodium-glucose co-transporter-2 (SGLT2) inhibitor licensed in the UK for the management of people with type 2 diabetes. SGLT2 inhibition in the proximal tubules of the nephron leads to increased urinary glucose excretion and reduced plasma glucose levels. All three SGLT2 inhibitors have been shown to reduce HbA1c by a similar amount. In addition, they produce a modest reduction in body weight and blood pressure. Adverse effects of SGLT2 inhibitors include an increased risk of genital infection, hypoglycaemia when used in combination with sulfonylureas and volume depletion when used in combination with diuretics. In addition, there have been safety warnings with respect to a risk of diabetic ketoacidosis with SGLT2 inhibitors and this has occurred with relatively low levels of blood glucose.
The results of one study have shown that in people with type 2 diabetes and a history of a previous cardiovascular event, empagliflozin reduced total and cardiovascular mortality compared with placebo. Hospitalisation due to heart failure was reduced with empagliflozin but outcomes relating to myocardial infarction and stroke did not reach statistical significance. It is not clear if the mortality benefits resulted from an effect on weight, blood pressure or cardiovascular load. However, the reduction in mortality does not appear to be due to an effect on atherosclerotic disease. The primary outcome for the pooled empagliflozin doses only just reached statistical significance for superiority and was not statistically significant for individual doses.
This is only the second randomised controlled study of an antidiabetic drug to demonstrate a reduction in cardiovascular events. Overall, the results are encouraging, particularly for people with type 2 diabetes and cardiovascular disease who are at high risk of heart failure. Nevertheless, a lack of evidence of longer-term outcomes in people at lower risk of cardiovascular disease and concerns over the safety profile of SGLT2 inhibitors suggest that clinicians should take a cautious approach until the benefits have been more clearly established.
References
[R= randomised controlled trial; M= meta-analysis]