Jardiance Mechanism of Action

Pharmacotherapeutic group: Sodium-glucose co-transporter 2 (SGLT2) inhibitors. ATC code: A10BK03.
Pharmacology: Mode of Action: Empagliflozin is a reversible competitive inhibitor of SGLT2 with an IC₅₀ of 1.3 nM. It has a 5000-fold selectivity over human SGLT1 (IC₅₀ of 6278 nM), 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 reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes mellitus (T2DM) and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.
Empagliflozin improves glycaemic control in patients with T2DM by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent upon the blood glucose concentration and GFR. Through inhibition of SGLT2 in patients with T2DM and hyperglycaemia, excess glucose is excreted in the urine.
In patients with T2DM, 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 4-week treatment period, averaging approximately 78 g/day with empagliflozin 25 mg once daily. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with T2DM.
Empagliflozin (10 mg and 25 mg) improves both fasting and post-prandial plasma glucose levels.
There is no direct effect on changes in β cell function and insulin secretion/action, and this contributes to a low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-B (HOMA-β) and proinsulin to insulin ratio were 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.
Clinical Trials: A total of 17331 patients with type 2 diabetes were evaluated 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 JARDIANCE for up to 102 weeks.
Treatment with empagliflozin (10 mg and 25 mg) as monotherapy and in combination with metformin, pioglitazone, and sulfonylurea lead to clinically relevant improvements in HbA1c, fasting plasma glucose (FPG), body weight, systolic and diastolic blood pressure (SBP and DBP, respectively). Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving an HbA1c goal of <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 in patients with eGFR >45mL/min/1.73m² (see Patients with Renal Impairment under Dosage & Administration). In patients aged 75 years and older, reduced efficacy of JARDIANCE was observed.
Empagliflozin as add on to metformin therapy: A double-blind, placebo-controlled study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in patients with type 2 diabetes not controlled on metformin. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in body weight and mean daily plasma glucose (MDG) after 24 weeks of treatment.
Treatment with JARDIANCE resulted in statistically significant improvements in HbA1c and body weight, and clinically meaningful reductions in FPG and blood pressure compared to placebo (Table 1).
In the double-blind placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.62% for empagliflozin 10 mg, -0.74% for empagliflozin 25 mg and -0.01% for placebo), body weight (change from baseline of -2.39 kg for empagliflozin 10 mg, -2.65 kg for empagliflozin 25 mg and -0.46 kg for placebo) and blood pressure (SBP: change from baseline of -5.2 mmHg for empagliflozin 10 mg, -4.5 mmHg for empagliflozin 25 mg and 0.8 mmHg for placebo, DBP: change from baseline of -2.5 mmHg for empagliflozin 10 mg, -1.9 mmHg for empagliflozin 25 mg and -0.5 mmHg for placebo) were sustained up to 76 weeks of treatment. (See Table 1.)


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Empagliflozin as add on to a combination of metformin and sulfonylureanylurea therapy: A double-blind, placebo-controlled study of 24 weeks duration was conducted to evaluate the efficacy and safety of empagliflozin in patients with type 2 diabetes not sufficiently treated with a combination of metformin and a sulfonylurea. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in body weight and mean daily plasma glucose (MDG) after 24 weeks of treatment. Treatment with JARDIANCE resulted in statistically significant improvements in HbA1c and body weight and clinically meaningful reductions in FPG and blood pressure compared to placebo (Table 2).
In the double-blind, placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.74% for empagliflozin 10 mg, -0.72% for empagliflozin 25 mg and -0.03% for placebo), body weight (change from baseline of -2.44 kg for empagliflozin 10 mg, -2.28 kg for empagliflozin 25 mg and -0.63 kg for placebo) and blood pressure (SBP: change from baseline of -3.8 mmHg for empagliflozin 10 mg, -3.7 mmHg for empagliflozin 25 mg and -1.6 mmHg for placebo, DBP: change from baseline of -2.6 mmHg for empagliflozin 10 mg, -2.3 mmHg for empagliflozin 25 mg and -1.4 mmHg for placebo) were sustained up to 76 weeks of treatment. (See Table 2.)


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2 hour post-prandial glucose: Treatment with empagliflozin (10 mg or 25 mg) as add-on to metformin or metformin plus sulfonylurea resulted in clinically meaningful improvement of 2-hour post-prandial glucose (meal tolerance test) at 24 weeks (add-on to metformin, placebo (n=57) +5.9 mg/dL, empagliflozin 10 mg (n=52): -46.0 mg/dl, empagliflozin 25 mg (n=58): -44.6 mg/dL; add-on to metformin plus sulfonylureanylurea, placebo (n=35): -2.3 mg/dL, empagliflozin 10 mg (n=44): -35.7 mg/dl, empagliflozin 25 mg (n=46): -36.6 mg/dL).
Empagliflozin as add on to a combination of metformin and pioglitazone therapy: The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo-controlled study of 24 weeks duration in patients with type 2 diabetes not controlled on a combination of metformin and pioglitazone. The primary endpoint was the change from baseline in HbA1c after 24 weeks of treatment. The key secondary endpoints were the change from baseline in FPG and body weight after 24 weeks of treatment.
Empagliflozin in combination with pioglitazone (dose ≥30 mg) with metformin resulted in statistically significant reductions in HbA1c, FPG, and body weight and clinically meaningful reductions in blood pressure compared to placebo (Table 3).
In the double-blind, placebo-controlled extension of this study, reductions of HbA1c (change from baseline of -0.61% for empagliflozin 10 mg, -0.70% for empagliflozin 25 mg and -0.01% for placebo), body weight (change from baseline of -1.47 kg for empagliflozin 10 mg, -1.21 kg for empagliflozin 25 mg and +0.50 kg for placebo) and blood pressure (SBP: change from baseline of -1.7 mmHg for empagliflozin 10 mg, -3.4 mmHg for empagliflozin 25 mg and +0.3 mmHg for placebo, DBP: change from baseline of -1.3 mmHg for empagliflozin 10 mg, -2.0 mmHg for empagliflozin 25 mg and +0.2 mmHg for placebo) were sustained up to 76 weeks of treatment. (See Table 3.)


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Empagliflozin 2-year data, as add on to metformin in comparison to glimepiride: In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (4 mg) in patients with inadequate glycaemic control on metformin alone, treatment with empagliflozin 25 mg daily resulted in superior reduction in HbA1c, and a clinically meaningful reduction in FPG, compared to glimepiride (Table 4). Empagliflozin 25 mg daily resulted in a statistically significant reduction in body weight, systolic and diastolic blood pressure (change from baseline in DBP of -1.8 mmHg for empagliflozin and +0.9 mmHg for glimepiride, p<0.0001).
Treatment with empagliflozin 25 mg daily resulted in statistically significantly lower proportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin 25 mg, 24.2% for glimepiride, p<0.0001). (See Table 4.)


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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 mild and moderate renal impairment in a double-blind, placebo-controlled study for 52 weeks.
Treatment with JARDIANCE led to statistically significant reduction of HbA1c and clinically meaningful improvement in FPG, body weight and BP compared to placebo at Week 24 (Table 5). The improvement in HbA1c, FPG, body weight, and blood pressure was sustained up to 52 weeks. (See Table 5.)


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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 (-3.27%) at week 24.
Body weight: In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin resulted in body weight reduction compared to placebo at week 24 (-2.04 kg for empagliflozin 10 mg, -2.26 kg for empagliflozin 25 mg and -0.24 kg for placebo) that was maintained up to week 52 (-1.96 kg for empagliflozin 10 mg, -2.25 kg for empagliflozin 25 mg and -0.16 kg for placebo).
Waist circumference: At 24 weeks, treatment with empagliflozin as monotherapy or as add-on to metformin, pioglitazone, or metformin plus sulfonylureanylurea resulted in sustained reduction of waist circumference over the duration of studies in a range of -1.7 cm to -0.9 cm for empagliflozin and -0.5 cm to +0.2 cm for placebo.
Blood pressure: The efficacy and safety of empagliflozin (10 mg and 25 mg) 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 oral antidiabetic drugs and up to 2 antihypertensive therapies (Table 6).
Treatment with empagliflozin once daily resulted in statistically significant improvement in HbA1c, 24 hour mean systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring. Treatment with empagliflozin provided reductions in seated SBP (change from baseline of -0.67 mmHg for placebo, -4.60 mmHg for empagliflozin 10 mg and -5.47 mmHg for empagliflozin 25 mg) and seated DBP (change from baseline of -1.13 mmHg for placebo, -3.06 mmHg for empagliflozin 10 mg and -3.02 mmHg for empagliflozin 25 mg). (See Table 6.)


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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.
Cardiovascular outcome: The EMPA-REG OUTCOME study is a multi-centre, multi-national, randomized, 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 7020 patients were treated with JARDIANCE (empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) 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 sulfonylureanylurea. The baseline HbA1c was <7% in 6.0% of the patients, 7 to <8% in 43.7% of the patients, 8 to <9% in 33.2% of the patients, and ≥9% in 17.0% of the patients. The time since diagnosis of diabetes was ≤5 years for 18.0% of the patients, >5 to 10 years for 24.9% of the patients, and >10 years for 57.1% of the patients.
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, and HDL 44 mg/dL. The urinary albumin to creatinine ratio (UACR) was normal in 59.4% of the patients, 28.7% had microalbuminuria, and 11% had macroalbuminuria.
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 incidence rate was 37.1 for JARDIANCE (10 and 25 mg, pooled) compared to 43.9 with placebo. The treatment effect reflected a significant reduction in cardiovascular death with no significant change in non-fatal MI, or non-fatal stroke (Table 7 and Figure 1).
JARDIANCE also improved all-cause mortality (Table 7), 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 7 and Figure 1.)


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Reductions 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 (see Table 8 and Figure 2).


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The cardiovascular benefits (CV death and hospitalisation for heart failure or CV death) of JARDIANCE observed were consistent across major demographic and disease subgroups.
Diabetic 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 9 and Figure 3).
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 9 and Figure 3.)


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Treatment 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 4).


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Thorough QTc study: In a randomized, placebo-controlled, active-comparator, crossover study of 30 healthy subjects, no increase in QTc was observed with either 25 mg or 200 mg empagliflozin.
Pharmacokinetics: Absorption: The pharmacokinetics of empagliflozin have been extensively characterized in healthy volunteers and patients with T2DM. After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations (Cmax) with a median time to reach Cmax (tmax) of 1.5 h 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 was 4740 nmol.h/L and C_max was 687 nmol/L with 25 mg empagliflozin once daily. Systemic exposure of empagliflozin increased in a dose-proportional manner. The single-dose and steady-state pharmacokinetics 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 T2DM.
Administration of 25 mg empagliflozin after intake of a high-fat and high calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C_max decreased 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 a population pharmacokinetic analysis. Following administration of an oral [¹⁴C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.
Metabolism: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, 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: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. 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 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 subjects, approximately 95.6% of the drug related radioactivity was eliminated in faeces (41.2%) or urine (54.4%). 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.
Specific Populations: Renal Impairment: In patients with mild (eGFR: 60 - <90 mL/min/1.73 m²), moderate (eGFR: 30 - <60 mL/min/1.73 m²), severe (eGFR: <30 mL/min/1.73 m²) renal impairment and patients with kidney failure/ESRD patients, 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. In line with the Phase I study, 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. However, due to the mechanism of action, the efficacy of JARDIANCE is dependent on renal function, and therefore JARDIANCE is contraindicated for use in patients with persistent eGFR <45mL/min/1.73m² (see Dosage & Administration, Contraindications and Precautions).
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 C_max by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function. Based on pharmacokinetics, no dosage adjustment is recommended in patients with hepatic impairment.
Body Mass Index (BMI): No dosage adjustment is necessary based on BMI. Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Gender: No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Race: No dosage adjustment is necessary based on race. Based on the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asian patients with a BMI of 25 kg/m² compared to non-Asian patients with a BMI of 25 kg/m².
Geriatric: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on the population pharmacokinetic analysis.
Paediatric: Studies characterizing the pharmacokinetics of empagliflozin in paediatric patients have not been performed.
Toxicology: 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, diarrhoea, 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.
Carcinogenicity: In a 2 year carcinogenicity study, empagliflozin did not increase the incidence of tumours 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 tumours 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 tumours are common in rats and are unlikely to be relevant to humans.
Empagliflozin did not increase the incidence of tumours 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 tumours 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 tumours 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 tumours are considered not relevant to humans.
Genotoxicity: Empagliflozin is not genotoxic.
Reproduction Toxicity: 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 a 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 100 mg/kg/day, which approximates 11-times the maximum clinical dose of 25 mg. These findings were absent after a 13 weeks drug-free recovery period.