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Pharmacology: Pharmacodynamics: 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 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 mild 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, and downregulating of sympathetic activity and reducing left ventricular wall stress as evidenced by lower NT-proBNP values and beneficial effects on cardiac remodeling, filling pressures and diastolic function. Other effects such as an increase in haematocrit, a reduction in body weight and blood pressure may further contribute to the beneficial effects observed independent of left ventricular ejection fraction (LVEF).
Clinical efficacy and safety: Type 2 diabetes mellitus: A total of 17331 patients with type 2 diabetes were treated in 15 double-blind, placebo- and active-controlled clinical studies, of which 4603 patients received empagliflozin 10 mg and 5567 received empagliflozin 25 mg. Six studies had a treatment duration of 24 weeks; in extensions of applicable studies, and other trials, patients were exposed to empagliflozin for up to 102 weeks.
Treatment with empagliflozin (10 mg and 25 mg) as monotherapy and in combination with metformin, pioglitazone, 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 (SBP and DBP, respectively). 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. There was a clinically meaningful improvement in HbA1c in all subgroups of gender, race, geographic region, time since diagnosis of T2DM, body mass index, insulin resistance based on HOMA-IR, and beta cell function based on HOMA-β. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Clinically meaningful HbA1c reduction was seen for patients with eGFR >30 mL/min/1.73 m2 (see Patients with renal impairment under Dosage & Administration). In patients aged 75 years and older, reduced efficacy of empagliflozin was observed.
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 1) and a clinically meaningful decrease in FPG.
In a pre-specified 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. (See Table 1.)
Click on icon to see table/diagram/imageCombination 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 2). 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. (See Table 2.)
Click on icon to see table/diagram/imageIn 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 improvement in HbA1c (Table 3) and led to greater reductions in FPG (compared to the individual components) and body weight (compared to metformin). (See Table 3.)
Click on icon to see table/diagram/imageEmpaglilfozin 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 4). In addition it resulted in clinically meaningful reductions in FPG, systolic and diastolic blood pressure compared to placebo. (See Table 4.)
Click on icon to see table/diagram/imageIn 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 5), 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). (See Table 5.)
Click on icon to see table/diagram/imageAdd-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 6).
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. (See Table 6.)
Click on icon to see table/diagram/imageEmpagliflozin 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 7).
At 78 weeks, empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparing compared to placebo. Furthermore, empagliflozin resulted in a reduction in FPG, body weight, and blood pressure. (See Table 7.)
Click on icon to see table/diagram/imagePatients 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 mild to moderate renal impairment in a double-blind, placebo-controlled study for 52 weeks. Treatment with empagliflozin led to a statistically significant reduction of HbA1c (Table 8) and clinically meaningful improvement in FPG, body weight and blood pressure compared to placebo at Week 24. The improvement in HbA1c, FPG, body weight, and blood pressure was sustained up to 52 weeks. (See Table 8.)
Click on icon to see table/diagram/imageFasting plasma glucose: In four placebo-controlled studies, treatment with empagliflozin as monotherapy or add-on therapy to metformin, pioglitazone, or metformin plus a sulphonylurea 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 9). Treatment with empagliflozin provided reductions in seated SBP and DBP. (See Table 9.)
Click on icon to see table/diagram/imageIn 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.
Cardiovascular outcome: The EMPA-REG OUTCOME study is a multi-centre, multi-national, randomised, double-blind, placebo-controlled trial investigating the effect of Jardiance as adjunct to standard care therapy in reducing cardiovascular events in patients with type 2 diabetes and one or more cardiovascular risk factors, including coronary artery disease, peripheral artery disease, history of myocardial infarction (MI), or history of stroke. The primary endpoint was the time to first event in the composite of CV death, nonfatal MI, or non-fatal stroke [(Major Adverse Cardiovascular Events (MACE-3)]. Additional pre-specified endpoints addressing clinically relevant outcomes tested in an exploratory manner included CV death, the composite of heart failure requiring hospitalisation or CV death, all-cause mortality and the composite of new or worsening nephropathy.
A total of 7,020 patients were treated with Jardiance (empagliflozin 10 mg: 2,345, empagliflozin 25 mg: 2,342, placebo: 2,333) and followed for a median of 3.1 years. The population was 72.4% Caucasian, 21.6% Asian, and 5.1% Black. The mean age was 63 years and 71.5% were male. At baseline, approximately 81% of patients were being treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 89% with anticoagulants, and 81% with lipid lowering medication. Approximately 74% of patients were being treated with metformin at baseline, 48% with insulin and 43% with sulphonylurea.
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. Mean systolic BP was 136 mmHg, diastolic BP 76 mmHg, LDL 86 mg/dL, HDL 44 mg/dL, and urinary albumin to creatinine ratio (UACR) 175 mg/g at baseline.
Reductions in risk of CV death and all-cause mortality: Jardiance was superior in reducing the primary composite endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke compared to placebo. The treatment effect reflected a significant reduction in cardiovascular death with no significant change in non-fatal MI, or non-fatal stroke (Table 8 and Figure 1).
Jardiance also improved overall survival (Table 10 and Figure 2), which was driven by a reduction in cardiovascular death with Jardiance. There was no statistically significant difference between empagliflozin and placebo in non-cardiovascular mortality. (See Table 10, Figures 1 and 2.)
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Click on icon to see table/diagram/imageReductions in risk of heart failure requiring hospitalization or CV death: Jardiance significantly reduced the risk of hospitalization for heart failure and cardiovascular death or hospitalization for heart failure compared with placebo (Table 11 and Figure 3). (See Table 11 and Figure 3.)
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Click on icon to see table/diagram/imageThe cardiovascular benefits of Jardiance observed were consistent across the subgroups depicted in Figure 4. (See Figure 4.)
Click on icon to see table/diagram/imageDiabetic kidney disease: In the EMPA-REG OUTCOME study population, the risk of new or worsening nephropathy [defined as onset of macroalbuminuria, doubling of serum creatinine, and initiation of renal replacement therapy (i.e. hemodialysis)] was significantly reduced in empagliflozin group compared to placebo (Table 12 and Figure 5).
Jardiance compared with placebo showed a significantly higher occurrence of sustained normo- or microalbuminuria in patients with baseline macroalbuminuria (HR 1.82, 95% CI 1.40, 2.37). (See Table 12 and Figure 5.)
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Click on icon to see table/diagram/imageTreatment with empagliflozin preserved eGFR and eGFR increased during the post treatment 4-week follow up. However, the placebo group showed a gradual decline in GFR during the course of the study with no further change during 4-week follow up (see Figure 6).
Click on icon to see table/diagram/imageThorough QTc study: In a randomised, placebo-controlled, active-comparator, crossover study of 30 healthy subjects, no increase in QTc was observed with either 25 mg or 200 mg empagliflozin.
Heart failure: Empagliflozin in patient with heart failure with 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 randomization, 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 hospitalization 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. (See Table 13, Figures 7 and 8.)
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Click on icon to see table/diagram/imageThe results of the primary composite endpoint were generally consistent with a hazard ratio (HR) below 1 across the pre-specified subgroups, including heart failure patients with and without type 2 diabetes mellitus (see Figure 9).
Click on icon to see table/diagram/imageRenal Outcome: During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (see Figure 10). Treatment with empagliflozin 10 mg significantly reduced the rate of eGFR decline and the effect was consistent across all pre-specified subgroups (see Table 13). Patients treated with empagliflozin experienced an initial drop in eGFR which returned towards baseline after treatment discontinuation supporting that haemodynamic changes play a role in the acute effects of empagliflozin on eGFR. (See Figure 10.)
Click on icon to see table/diagram/imageJardiance reduced the risk of the renal composite endpoint defined as time to first event of chronic dialysis or renal transplant or sustained reduction in eGFR compared with placebo (Table 14 and Figure 11). (See Table 14 and Figure 11.)
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Click on icon to see table/diagram/imageThe effect of empagliflozin on heart failure symptoms at week 52 was assessed as a patient-reported outcome using the change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS), which measures average of symptom frequency and burden for swelling, fatigue, and shortness of breath and physical limitations.
There was a greater improvement in the clinical summary score from baseline in the empagliflozin group than in the placebo group at Week 52 (placebo-corrected adjusted mean change from baseline 1.75, 95% CI 0.51 to 2.99, nominal p-value = 0.0058), driven by all domains included (symptom frequency, symptom burden, and physical limitations).
Empagliflozin in patients with heart failure and preserved ejection fraction: A randomised, double-blind, placebo-controlled study (EMPEROR-Preserved) was conducted in 5988 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 receptor-neprilysin inhibitor (80.7%), beta blockers (86.3%), mineralocorticoid receptor antagonists (37.5%) and diuretics (86.2%).
A total of 2997 patients were randomised to empagliflozin 10 mg (placebo: 2991) 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 hospitalization 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. (see Table 15, Figure 12 and 13.)
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Click on icon to see table/diagram/imageThe 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 (see Figure 14).
Click on icon to see table/diagram/imageRenal Outcome: During treatment, eGFR decline over time was slower in the empagliflozin group compared to the placebo group (see Figure 15). Treatment with empagliflozin 10 mg significantly reduced the rate of eGFR decline and the effect was consistent across all pre-specified subgroups (see Table 16). Patients treated with empagliflozin experienced an initial drop in eGFR which returned towards baseline after treatment discontinuation supporting that haemodynamic changes play a role in the acute effects of empagliflozin on eGFR. (See Figure 15.)
Click on icon to see table/diagram/imageIn an analysis of the composite renal endpoint (defined as time to first event of chronic dialysis or renal transplant or sustained reduction in eGFR) the hazard ratio was 0.95 (95% CI 0.73 to 1.24, nominal p-value 0.7243).
The effect of empagliflozin on heart failure symptoms at week 52 was assessed as a patient-reported outcome using the change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS), which measures average of symptom frequency and burden for swelling, fatigue, and shortness of breath and physical limitations.
There was a greater improvement in the clinical summary score from baseline in the empagliflozin group than in the placebo group at Week 52 (placebo-corrected adjusted mean change from baseline 1.32, 95% CI 0.45 to 2.19, nominal p-value = 0.0028), driven by the domains symptom frequency and symptom burden.
Pharmacokinetics: Absorption: The pharmacokinetics of empagliflozin have been extensively characterised in healthy volunteers and patients with type 2 diabetes. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median tmax of 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol.h/l and 259 nmol/l with empagliflozin 10 mg and 4740 nmol.h/l and 687 nmol/l with empagliflozin 25 mg once daily. Systemic exposure of empagliflozin increased in a dose-proportional manner. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar suggesting linear pharmacokinetics with respect to time. There were no clinically relevant differences in empagliflozin pharmacokinetics between healthy volunteers and patients with type 2 diabetes.
Administration of empagliflozin 25 mg after intake of a high-fat and high calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax by approximately 37% compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.
Distribution: The apparent steady-state volume of distribution was estimated to be 73.8 l based on the population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy volunteers, the red blood cell partitioning was approximately 37% and plasma protein binding was 86%.
Metabolism: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-, 3-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
Elimination: Based on the population pharmacokinetic analysis, the apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 hours and apparent oral clearance was 10.6 l/hour. The inter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%, respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent with the half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [14C]-empagliflozin solution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated in faeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
Special populations: Renal impairment: In patients with mild (eGFR: 60 - < 90 ml/min/1.73 m2), moderate (eGFR: 30 - < 60 ml/min/1.73 m2) or severe renal impairment (eGFR <30 ml/min/1.73 m2) and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. The population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure. Based on pharmacokinetics, no dosage adjustment is recommended in patients with renal insufficiency (see Dosage & Administration).
Hepatic impairment: In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and Cmax by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.
Body Mass Index: Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis. In this analysis, AUC was estimated to be 5.82%, 10.4%, and 17.3% lower in subjects with BMI of 30, 35, and 45 kg/m2, respectively, compared to subjects with a body mass index of 25 kg/m2.
Gender: Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Race: In the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asians with a body mass index of 25 kg/m2 compared to non-Asians with a body mass index of 25 kg/m2.
Elderly patients: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Paediatric patients: Studies characterising the pharmacokinetics of empagliflozin in paediatric patients have not been performed.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, fertility and early embryonic development.
In long term toxicity studies in rodents and dogs, signs of toxicity were observed at exposures greater than or equal to 10-times the clinical dose of empagliflozin. Most toxicity was consistent with secondary pharmacology related to urinary glucose loss and electrolyte imbalances including decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein metabolism and gluconeogenesis, urinary changes such as polyuria and glucosuria, and microscopic changes including mineralisation in kidney and some soft and vascular tissues. Microscopic evidence of the effects of exaggerated pharmacology on the kidney observed in some species included tubular dilatation, and tubular and pelvic mineralisation at approximately 4-times the clinical AUC exposure of empagliflozin associated with the 25 mg dose.
Empagliflozin is not genotoxic.
In a 2 year carcinogenicity study, empagliflozin did not increase the incidence of tumors in female rats up to the highest dose of 700 mg/kg/day, which corresponds to approximately 72-times the maximal clinical AUC exposure to empagliflozin. In male rats, treatment-related benign vascular proliferative lesions (haemangiomas) of the mesenteric lymph node were observed at the highest dose, but not at 300 mg/kg/day, which corresponds to approximately 26-times the maximal clinical exposure to empagliflozin. Interstitial cell tumors in the testes were observed with a higher incidence in rats at 300 mg/kg/day and above, but not at 100 mg/kg/day which corresponds to approximately 18-times the maximal clinical exposure to empagliflozin. Both tumors are common in rats and are unlikely to be relevant to humans.
Empagliflozin did not increase the incidence of tumors in female mice at doses up to 1000 mg/kg/day, which corresponds to approximately 62-times the maximal clinical exposure to empagliflozin. Empagliflozin induced renal tumors in male mice at 1000 mg/kg/day, but not at 300 mg/kg/day, which corresponds to approximately 11-times the maximal clinical exposure to empagliflozin. The mode of action for these tumors is dependent on the natural predisposition of the male mouse to renal pathology and a metabolic pathway not reflective of humans. The male mouse renal tumors are considered not relevant to humans.
At exposures sufficiently in excess of exposure in humans after therapeutic doses, empagliflozin had no adverse effects on fertility or early embryonic development. Empagliflozin administered during the period of organogenesis was not teratogenic. Only at maternally toxic doses, empagliflozin also caused bent limb bones in the rat and increased embryofetal loss in the rabbit.
In pre- and postnatal toxicity studies in rats, reduced weight gain of offspring was observed at maternal exposures approximately 4-times the maximal clinical exposure to empagliflozin. No such effect was seen at systemic exposure equal to the maximal clinical exposure to empagliflozin. The relevance of this finding to humans is unclear.
In juvenile toxicity study in the rat, when empagliflozin was administered from postnatal day 21 until postnatal day 90, non-adverse, minimal to mild renal tubular and pelvic dilation in juvenile rats was seen only at 100mg/kg/day, which approximates 11-times the maximum clinical dose of 25 mg. The findings were absent after a 13 weeks drug-free recovery period.
