JARDIANCE Film-coated tablet Ref.[7237] Active ingredients: Empagliflozin

Pharmacotherapeutic group: Drugs used in diabetes, Other blood glucose lowering drugs, excl. insulins
ATC code: A10BK03

Mechanism of action

Empagliflozin is a reversible, highly potent (IC₅₀ of 1.3 nmol) and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5000 times more selective for SGLT2 versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, as the predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.

Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and hyperglycaemia leads to excess glucose excretion in the urine. In addition, initiation of empagliflozin increases excretion of sodium resulting in osmotic diuresis and reduced intravascular volume.

In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first dose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of the 4-week treatment period, averaging approximately 78 g/day. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with type 2 diabetes.

Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism of action of empagliflozin is independent of beta cell function and insulin pathway and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction. The glucosuria observed with empagliflozin is accompanied by diuresis which may contribute to sustained and moderate reduction of blood pressure.

Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to: increasing tubuloglomerular feedback and reducing intraglomerular pressure, lowering both pre- and afterload of the heart, downregulating of sympathetic activity and reducing left ventricular wall stress as evidenced by lower NT-proBNP values which may have beneficial effects on cardiac remodeling, filling pressures and diastolic function as well as preserving kidney structure and function. Other effects such as an increase in haematocrit, a reduction in body weight and blood pressure may further contribute to the beneficial cardiac and renal effects.

Clinical efficacy and safety

Type 2 diabetes mellitus

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are an integral part of the treatment of type 2 diabetes.

Glycaemic efficacy and cardiovascular outcomes have been assessed in a total of 14,663 patients with type 2 diabetes who were treated in 12 double-blind, placebo- and active-controlled clinical studies, of which 9,295 received empagliflozin (empagliflozin 10 mg: 4,165 patients; empagliflozin 25 mg: 5,130 patients). Five studies had treatment durations of 24 weeks; extensions of those and other studies had patients exposed to empagliflozin for up to 102 weeks.

Treatment with empagliflozin as monotherapy and in combination with metformin, pioglitazone, a sulphonylurea, DPP-4 inhibitors, and insulin lead to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, and systolic and diastolic blood pressure. Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving HbA1c goal of less than 7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo. Higher baseline HbA1c was associated with a greater reduction in HbA1c. In addition, empagliflozin as adjunct to standard care therapy reduced cardiovascular mortality in patients with type 2 diabetes and established cardiovascular disease.

Monotherapy

The efficacy and safety of empagliflozin as monotherapy was evaluated in a double-blind, placebo- and active-controlled study of 24 weeks duration in treatment-naïve patients. Treatment with empagliflozin resulted in a statistically significant (p<0.0001) reduction in HbA1c compared to placebo (Table 2) and a clinically meaningful decrease in FPG. In a prespecified analysis of patients (N=201) with a baseline HbA1c ≥8.5%, treatment resulted in a reduction in HbA1c from baseline of -1.44% for empagliflozin 10 mg, -1.43% for empagliflozin 25 mg, -1.04% for sitagliptin, and an increase of 0.01% for placebo. In the double-blind placebo-controlled extension of this study, reductions of HbA1c, body weight and blood pressure were sustained up to Week 76.

Table 2. Efficacy results of a 24 week placebo-controlled study of empagliflozin as monotherapy^a:

^a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescue therapy
¹ Mean adjusted for baseline value
² Not evaluated for statistical significance as a result of the sequential confirmatory testing procedure
³ 95% CI
⁴ LOCF, values after antihypertensive rescue censored
* p-value<0.0001

Combination therapy

Empagliflozin as add-on to metformin, sulphonylurea, pioglitazone:

Empagliflozin as add-on to metformin, metformin and a sulphonylurea, or pioglitazone with or without metformin resulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared to placebo (Table 3). In addition it resulted in a clinically meaningful reduction in FPG, systolic and diastolic blood pressure compared to placebo. In the double-blind placebo-controlled extension of these studies, reduction of HbA1c, body weight and blood pressure were sustained up to Week 76.

Table 3. Efficacy results of 24 week placebo-controlled studies^a:

^a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescue therapy
¹ Mean adjusted for baseline value
² Not evaluated for statistical significance as a result of the sequential confirmatory testing procedure
³ LOCF, values after antihypertensive rescue censored
^* p-value <0.0001

In combination with metformin in drug-naïve patients:

A factorial design study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in drug-naïve patients. Treatment with empagliflozin in combination with metformin (5 mg and 500 mg; 5 mg and 1000 mg; 12.5 mg and 500 mg, and 12.5 mg and 1000 mg given twice daily) provided statistically significant improvements in HbA1c (Table 4) and led to greater reductions in FPG (compared to the individual components) and body weight (compared to metformin).

Table 4. Efficacy results at 24 week comparing empagliflozin in combination with metformin to the individual components^a:

Met = metformin; empa = empagliflozin
¹ mean adjusted for baseline value
^a Analyses were performed on the full analysis set (FAS) using an observed cases (OC) approach
^b Given in two equally divided doses per day when given together with metformin
^c Given in two equally divided doses per day
* p≤0.0062 for HbA1c

Empagliflozin in patients inadequately controlled with metformin and linagliptin:

In patients inadequately controlled with metformin and linagliptin 5 mg, treatment with both empagliflozin 10 mg or 25 mg resulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared to placebo (Table 5). In addition it resulted in clinically meaningful reductions in FPG, systolic and diastolic blood pressure compared to placebo.

Table 5. Efficacy results of a 24 week placebo-controlled study in patients inadequately controlled with metformin and linagliptin 5 mg:

¹ Mean adjusted for baseline value
² Not evaluated for statistical significance; not part of sequential testing procedure for the secondary endpoints
³ MMRM model on FAS (OC) included baseline HbA1c, baseline eGFR (MDRD), geographical region, visit, treatment, and treatment by visit interaction. For weight, baseline weight was included.
⁴ MMRM model included baseline SBP and baseline HbA1c as linear covariate(s), and baseline eGFR, geographical region, treatment, visit, and visit by treatment interaction as fixed effects.
⁵ Patients randomized to the placebo group were receiving the placebo plus linagliptin 5 mg with background metformin
⁶ Patients randomized to the empagliflozin 10 mg or 25 mg groups were receiving empagliflozin 10 mg or 25 mg and linagliptin 5 mg with background metformin
* p-value <0.0001

In a prespecified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reduction from baseline in HbA1c was -1.3% with empagliflozin 10 mg or 25 mg at 24 weeks (p<0.0001) compared to placebo.

Empagliflozin 24 months data, as add-on to metformin in comparison to glimepiride:

In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (up to 4 mg per day) in patients with inadequate glycaemic control on metformin alone, treatment with empagliflozin daily resulted in superior reduction in HbA1c (Table 6), and a clinically meaningful reduction in FPG, compared to glimepiride. Empagliflozin daily resulted in a statistically significant reduction in body weight, systolic and diastolic blood pressure and a statistically significantly lower proportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin, 24.2% for glimepiride, p<0.0001).

Table 6. Efficacy results at 104 week in an active controlled study comparing empagliflozin to glimepiride as add-on to metformin^a:

^a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescue therapy
^b Up to 4 mg glimepiride
¹ Mean adjusted for baseline value
² LOCF, values after antihypertensive rescue censored
* p-value <0.0001 for non-inferiority, and p-value =0.0153 for superiority
** p-value <0.0001

Add-on to insulin therapy:

Empagliflozin as add-on to multiple daily insulin:

The efficacy and safety of empagliflozin as add-on to multiple daily insulin with or without concomitant metformin therapy was evaluated in a double-blind, placebo-controlled trial of 52 weeks duration. During the initial 18 weeks and the last 12 weeks, the insulin dose was kept stable, but was adjusted to achieve pre-prandial glucose levels <100 mg/dl [5.5 mmol/l], and post-prandial glucose levels <140 mg/dl [7.8 mmol/l] between Weeks 19 and 40.

At Week 18, empagliflozin provided statistically significant improvement in HbA1c compared with placebo (Table 7).

At Week 52, treatment with empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared with placebo and a reduction in FPG and body weight.

Table 7. Efficacy results at 18 and 52 weeks in a placebo-controlled study of empagliflozin as add on to multiple daily doses of insulin with or without metformin:

¹ Mean adjusted for baseline value
² Week 19-40: treat-to-target regimen for insulin dose adjustment to achieve pre-defined glucose target levels (pre-prandial <100 mg/dl (5.5 mmol/l), post-prandial <140 mg/dl (7.8 mmol/l)
* p-value <0.0001
** p-value =0.0003
*** p-value =0.0005
^# p-value =0.0040

Empagliflozin as add-on to basal insulin

The efficacy and safety of empagliflozin as add-on to basal insulin with or without metformin and/or a sulphonylurea was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. During the initial 18 weeks the insulin dose was kept stable, but was adjusted to achieve a FPG <110 mg/dl in the following 60 weeks.

At week 18, empagliflozin provided statistically significant improvement in HbA1c (Table 8).

At 78 weeks, empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing

Table 8. Efficacy results at 18 and 78 weeks in a placebo-controlled study of empagliflozin as add-on to basal insulin with or without metformin or a sulphonylurea^a:

^a Full analysis set (FAS) - Completers using last observation carried forward (LOCF) prior to glycaemic rescue therapy
¹ mean adjusted for baseline value
* p-value <0.0001
** p-value <0.025

Patients with renal impairment, 52 week placebo controlled data:

The efficacy and safety of empagliflozin as add-on to antidiabetic therapy was evaluated in patients with renal impairment in a double-blind, placebo-controlled study for 52 weeks. Treatment with empagliflozin led to a statistically significant reduction of HbA1c (Table 9) and clinically meaningful improvement in FPG compared to placebo at Week 24. The improvement in HbA1c, body weight, and blood pressure was sustained up to 52 weeks. compared to placebo. Furthermore, empagliflozin resulted in a reduction in FPG, body weight, and blood pressure.

Table 9. Results at 24 week in a placebo-controlled study of empagliflozin in renally impaired type 2 diabetes patients^a:

^a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescue therapy
¹ Mean adjusted for baseline value
² Not evaluated for statistical significance as a result of the sequential confirmatory testing procedure
* p<0.0001

Cardiovascular outcome:

The double-blind, placebo-controlled EMPA-REG OUTCOME study compared pooled doses of empagliflozin 10 mg and 25 mg with placebo as adjunct to standard care therapy in patients with type 2 diabetes and established cardiovascular disease. A total of 7020 patients were treated (empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of 3.1 years. The mean age was 63 years, the mean HbA1c was 8.1%, and 71.5% were male. At baseline, 74% of patients were being treated with metformin, 48% with insulin, and 43% with a sulfonylurea. About half of the patients (52.2%) had an eGFR of 60-90 ml/min/1.73 m², 17.8% of 45-60 ml/min/1.73 m² and 7.7% of 30-45 ml/min/1.73 m².

At week 12, an adjusted mean (SE) improvement in HbA1c when compared to baseline of 0.11% (0.02) in the placebo group, 0.65% (0.02) and 0.71% (0.02) in the empagliflozin 10 and 25 mg groups was observed. After the first 12 weeks glycaemic control was optimized independent of investigative treatment. Therefore the effect was attenuated at week 94, with an adjusted mean (SE) improvement in HbA1c of 0.08% (0.02) in the placebo group, 0.50% (0.02) and 0.55% (0.02) in the empagliflozin 10 and 25 mg groups.

Empagliflozin was superior in preventing the primary combined endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, as compared with placebo. The treatment effect was driven by a significant reduction in cardiovascular death with no significant change in non-fatal myocardial infarction, or non-fatal stroke. The reduction of cardiovascular death was comparable for empagliflozin 10 mg and 25 mg (Figure 1) and confirmed by an improved overall survival (Table 10).

The efficacy for preventing cardiovascular mortality has not been conclusively established in patients using empagliflozin concomitantly with DPP-4 inhibitors or in Black patients because the representation of these groups in the EMPA-REG OUTCOME study was limited.

Table 10. Treatment effect for the primary composite endpoint, its components and mortality^a:

CV = cardiovascular, MI = myocardial infarction
^a Treated set (TS), i.e. patients who had received at least one dose of study drug
^b Pooled doses of empagliflozin 10 mg and 25 mg
* Since data from the trial were included in an interim analysis, a two-sided 95.02% confidence interval applied which corresponds to a p-value of less than 0.0498 for significance.

Figure 1. Time to occurrence of cardiovascular death in the EMPA-REG OUTCOME study:

Heart failure requiring hospitalization

In the EMPA-REG OUTCOME study, empagliflozin reduced the risk of heart failure requiring hospitalization compared with placebo (empagliflozin 2.7 %; placebo 4.1 %; HR 0.65, 95 % CI 0.50, 0.85).

Nephropathy

In the EMPA-REG OUTCOME study, for time to first nephropathy event, the HR was 0.61 (95 % CI 0.53, 0.70) for empagliflozin (12.7 %) vs placebo (18.8 %).

In addition, empagliflozin showed a higher (HR 1.82, 95 % CI 1.40, 2.37) occurrence of sustained normo- or micro-albuminuria (49.7 %) in patients with baseline macro-albuminuria compared with placebo (28.8 %).

Fasting plasma glucose:

In four placebo-controlled studies, treatment with empagliflozin as monotherapy or add-on therapy to metformin, pioglitazone, or metformin plus a sulfonylurea resulted in mean changes from baseline in FPG of -20.5 mg/dl [-1.14 mmol/l] for empagliflozin 10 mg and -23.2 mg/dl [-1.29 mmol/l] for empagliflozin 25 mg compared to placebo (7.4 mg/dl [0.41 mmol/l]). This effect was observed after 24 weeks and maintained for 76 weeks.

2-hour post-prandial glucose:

Treatment with empagliflozin as add-on to metformin or metformin and a sulphonylurea resulted in a clinically meaningful reduction of 2-hour post-prandial glucose (meal tolerance test) at 24 weeks (add-on to metformin: placebo +5.9 mg/dl, empagliflozin 10 mg: -46.0 mg/dl, empagliflozin 25 mg: -44.6 mg/dl, add-on to metformin and a sulphonylurea: placebo -2.3 mg/dl, empagliflozin 10 mg: -35.7 mg/dl, empagliflozin 25 mg: -36.6 mg/dl).

Patients with high baseline HbA1c >10%:

In a pre-specified pooled analysis of three phase 3 studies, treatment with open-label empagliflozin 25 mg in patients with severe hyperglycaemia (N=184, mean baseline HbA1c 11.15%) resulted in a clinically meaningful reduction in HbA1c from baseline of 3.27% at week 24; no placebo or empagliflozin 10 mg arms were included in these studies.

Body weight:

In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin resulted in body weight reduction (-0.24 kg for placebo, -2.04 kg for empagliflozin 10 mg and -2.26 kg for empagliflozin 25 mg) at week 24 that was maintained up to week 52 (-0.16 kg for placebo, -1.96 kg for empagliflozin 10 mg and -2.25 kg for empagliflozin 25 mg).

Blood pressure:

The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo controlled study of 12 weeks duration in patients with type 2 diabetes and high blood pressure on different antidiabetic and up to 2 antihypertensive therapies. Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c, and 24 hour mean systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring (Table 11). Treatment with empagliflozin provided reductions in seated SBP and DBP.

Table 11. Efficacy results at 12 week in a placebo-controlled study of empagliflozin in patients with type 2 diabetes and uncontrolled blood pressure^a:

^a Full analysis set (FAS)
¹ LOCF, values after taking antidiabetic rescue therapy censored
² Mean adjusted for baseline HbA1c, baseline eGFR, geographical region and number of antihypertensive medicinal products
³ LOCF, values after taking antidiabetic rescue therapy or changing antihypertensive rescue therapy censored
⁴ Mean adjusted for baseline SBP, baseline HbA1c, baseline eGFR, geographical region and number of antihypertensive medicinal products
⁵ Mean adjusted for baseline DBP, baseline HbA1c, baseline eGFR, geographical region and number of antihypertensive medicinal products
* p-value <0.0001
** p-value <0.001

In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin resulted in a reduction in systolic blood pressure (empagliflozin 10 mg: -3.9 mmHg; empagliflozin 25 mg: -4.3 mmHg) compared with placebo (-0.5 mmHg) and in diastolic blood pressure (empagliflozin 10 mg: -1.8 mmHg; empagliflozin 25 mg: -2.0 mmHg) compared with placebo (-0.5 mmHg) at week 24 that were maintained up to week 52.

Heart failure

Empagliflozin in patients with heart failure and reduced ejection fraction

A randomised, double-blind, placebo-controlled study (EMPEROR-Reduced) was conducted in 3 730 patients with chronic heart failure (New York Heart Association [NYHA] II-IV) and reduced ejection fraction (LVEF ≤40%) to evaluate the efficacy and safety of empagliflozin 10 mg once daily as adjunct to standard of care heart failure therapy. The primary endpoint was the time to adjudicated first event of either cardiovascular (CV) death or hospitalisation for heart failure (HHF). Occurrence of adjudicated HHF (first and recurrent) and eGFR (CKD-EPI)cr slope of change from baseline were included in the confirmatory testing. Heart Failure therapy at baseline included ACE inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (88.3%), beta blockers (94.7%), mineralocorticoid receptor antagonists (71.3%) and diuretics (95.0%).

A total of 1 863 patients were randomised to empagliflozin 10 mg (placebo: 1 867) and followed for a median of 15.7 months. The study population consisted of 76.1% men and 23.9% women with a mean age of 66.8 years (range: 25-94 years), 26.8% were 75 years of age or older. 70.5% of the study population were White, 18.0% Asian and 6.9% Black/African American. At randomisation, 75.1% of patients were NYHA class II, 24.4% were class III and 0.5% were class IV. The mean LVEF was 27.5%. At baseline, the mean eGFR was 62.0 ml/min/1.73 m² and the median urinary albumin to
creatinine ratio (UACR) was 22 mg/g. About half of the patients (51.7%) had an eGFR of ≥60 ml/min/1.73 m², 24.1% of 45 to <60 ml/min/1.73 m², 18.6% of 30 to <45 ml/min/1.73 m² and 5.3% 20 to <30 ml/min/1.73 m².

Empagliflozin was superior in reducing the risk of the primary composite endpoint of cardiovascular death or hospitalisation for heart failure compared with placebo. Additionally, empagliflozin significantly reduced the risk of occurrence of HHF (first and recurrent), and significantly reduced the rate of eGFR decline (Table 12; Figure 2).

Table 12. Treatment effect for the primary composite endpoint, its components and the two key secondary endpoints included in the pre-specified confirmatory testing:

CV = cardiovascular, HHF = hospitalisation for heart failure, eGFR = Estimated glomerular filtration rate, CKD EPI = Chronic kidney disease epidemiology collaboration equation
^* CV death and HHF events were adjudicated by an independent clinical event committee and analysed based on the randomised set.
^** eGFR slope was analysed based on the treated set. Intercept is -0.95 ml/min/1.73 m² for placebo and -3.02 ml/min/1.73 m² for empagliflozin. The intercept represents the acute effect on eGFR while the slope represents the long-term effect.

Figure 2. Time to first event of adjudicated CV death or HHF:

The results of the primary composite endpoint were generally consistent with a hazard ratio (HR) below 1 across the pre-specified subgroups, including patients with heart failure, with or without type 2 diabetes mellitus and with or without renal impairment (down to an eGFR of 20 ml/min/1.73 m²).

Empagliflozin in patients with heart failure and preserved ejection fraction

A randomised, double-blind, placebo-controlled study (EMPEROR-Preserved) was conducted in 5 988 patients with chronic heart failure (NYHA II-IV) and preserved ejection fraction (LVEF >40%) to evaluate the efficacy and safety of empagliflozin 10 mg once daily as adjunct to standard of care therapy. The primary endpoint was the time to adjudicated first event of either cardiovascular (CV) death or hospitalisation for heart failure (HHF). Occurrence of adjudicated HHF (first and recurrent), and eGFR (CKD-EPI)cr slope of change from baseline were included in the confirmatory testing. Baseline therapy included ACE inhibitors/angiotensin receptor blockers/angiotensin receptorneprilysin inhibitor (80.7%), beta blockers (86.3%), mineralocorticoid receptor antagonists (37.5%) and diuretics (86.2%).

A total of 2 997 patients were randomised to empagliflozin 10 mg (placebo: 2 991) and followed for a median of 26.2 months. The study population consisted of 55.3% men and 44.7% women with a mean age of 71.9 years (range: 22-100 years), 43.0% were 75 years of age or older. 75.9% of the study population were White, 13.8% Asian and 4.3% Black/African American. At randomisation, 81.5% of patients were NYHA class II, 18.1% were class III and 0.3% were class IV. The EMPEROR-Preserved study population included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60% (34.4%) and a LVEF ≥60% (32.5%). At baseline, the mean eGFR was 60.6 ml/min/1.73 m² and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g. About half of the patients (50.1%) had an eGFR of ≥60 ml/min/1.73 m², 26.1% of 45 to <60 ml/min/1.73 m², 18.6% of 30 to <45 ml/min/1.73 m² and 4.9% 20 to <30 ml/min/1.73 m².

Empagliflozin was superior in reducing the risk of the primary composite endpoint of cardiovascular death or hospitalisation for heart failure compared with placebo. Additionally, empagliflozin significantly reduced the risk of occurrence of HHF (first and recurrent), and significantly reduced the rate of eGFR decline (Table 13; Figure 3).

Table 13. Treatment effect for the primary composite endpoint, its components and the two key secondary endpoints included in the pre-specified confirmatory testing:

CV = cardiovascular, HHF = hospitalisation for heart failure, eGFR = Estimated glomerular filtration rate, CKD EPI = Chronic kidney disease epidemiology collaboration equation
^* CV death and HHF events were adjudicated by an independent clinical event committee and analysed based on the randomised set.
^** eGFR slope was analysed based on the treated set. Intercept is -0.18 ml/min/1.73 m² for placebo and -3.02 ml/min/1.73 m² for empagliflozin. The intercept represents the acute effect on eGFR while the slope represents the long-term effect.

Figure 3. Time to first event of adjudicated CV death or HHF:

The results of the primary composite endpoint were consistent across each of the pre-specified subgroups categorized by e.g., LVEF, diabetes status or renal function (down to an eGFR of 20 ml/min/1.73 m²).

Chronic kidney disease

A randomised, double-blind, placebo-controlled study of empagliflozin 10 mg once daily (EMPAKIDNEY) was conducted in 6 609 patients with chronic kidney disease (eGFR ≥20 - <45 ml/min/1.73 m²; or eGFR ≥45 - <90 ml/min/1.73 m² with urinary albumin to creatinine ratio (UACR) ≥200 mg/g) to assess cardio-renal outcomes as adjunct to standard of care therapy. The primary endpoint was the time to first occurrence of kidney disease progression (sustained ≥40% eGFR decline from randomisation, sustained eGFR <10 ml/min/1.73 m², end-stage kidney disease, or renal death) or CV death. First occurrence of hospitalisation for heart failure or CV death, all-cause hospitalisation (first and recurrent), and all-cause mortality were included in the confirmatory testing. Baseline therapy included an appropriate use of a RAS-inhibitor (85.2% ACE inhibitor or angiotensin receptor blocker).

A total of 3 304 patients were randomised to empagliflozin 10 mg (placebo: 3 305) and followed for a median of 24.3 months. The study population consisted of 66.8% men and 33.2% women with a mean age of 63.3 years (range: 18-94 years), 23.0% were 75 years of age or older. 58.4% of the study population were White, 36.2% Asian and 4.0% Black/African American.

At baseline, the mean eGFR was 37.3 ml/min/1.73 m², 21.2% patients had an eGFR of
≥45 ml/min/1.73 m², 44.3% of 30 to <45 ml/min/1.73 m² and 34.5% <30 ml/min/1.73 m² including 254 patients with an eGFR <20 ml/min /1.73 m². The median UACR was 329 mg/g, 20.1% patients had an UACR <30 mg/g, 28.2% had an UACR 30 to ≤300 mg/g and 51.7% had an UACR >300 mg/g; 41.1% of patients had an UACR <200 mg/g. Primary causes of CKD were diabetic nephropathy/diabetic kidney disease (31%), glomerular disease (25%), hypertensive/renovascular disease (22%) and other/unknown (22%).

Empagliflozin was superior in reducing the risk of the primary composite endpoint of kidney disease progression or CV death compared with placebo (see Table 14). Additionally, empagliflozin significantly reduced the risk of all-cause hospitalisation (first and recurrent).

Table 14. Treatment effect for the primary composite and key secondary endpoints included in the prespecified confirmatory testing and its components:

CV = cardiovascular, HHF = hospitalisation for heart failure, eGFR = Estimated glomerular filtration rate
^* End-stage kidney disease (ESKD) is defined as the initiation of maintenance dialysis or receipt of a kidney transplant.
^** There were too few events of renal death to compute a reliable hazard ratio.
^# Predefined as one of the two stopping criteria in the pre-planned interim analysis.

Figure 4. Time to first event of kidney disease progression or adjudicated CV death, estimated cumulative incidence function:

The results of the primary composite endpoint were generally consistent across the pre-specified subgroups, including eGFR categories, underlying cause of renal disease, diabetes status, or background use of RAS inhibitors. Treatment benefits were more clearly evident in patients with higher levels of albuminuria.

During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (Figure 5). Empagliflozin slowed the annual rate of eGFR decline compared to placebo by 1.37 ml/min/1.73 m²/year (95% CI 1.16, 1.59), based on a pre-specified analysis of all eGFR measurements taken from the 2-month visit to the final follow-up visit. Patients treated with empagliflozin experienced an initial drop in eGFR which returned towards baseline after treatment discontinuation as demonstrated in several of the empagliflozin studies, supporting that haemodynamic changes play a role in the acute effects of empagliflozin on eGFR.

Figure 5. Change in eGFR over time*:

^* eGFR (CKD-EPI) (ml/min/1.73 m²

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Jardiance in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with Jardiance in all subsets of the paediatric population in heart failure (see section 4.2 for information on paediatric use).

The European Medicines Agency has waived the obligation to submit the results of studies with Jardiance in all subsets of the paediatric population in chronic kidney disease (see section 4.2 for information on paediatric use).