Summary Basis of Decision for Jardiance

 

Clinical Pharmacology

Sodium-glucose co-transporter 2 (SGLT) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. By inhibiting SGLT2 reversibly, empagliflozin (the active ingredient of Jardiance) reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Empagliflozin accumulates up to 22% based on exposure and exhibited dose proportional pharmacokinetics in the dose range of 2.5 to 100 mg and is cleared equally by renal and hepatic mechanisms.

The exposures and maximal concentrations of empagliflozin were increased by 75% and 48% in patients with severe hepatic impairment and based on increases in hepatic enzymes observed in clinical trials, empagliflozin is not recommended in patients with severe hepatic impairment.

Empagliflozin does not inhibit, inactivate or induce cytochrome P40 (CYP450) isoforms, uridine 5'-diphospho-glucuronosyltransferase (UGT1A1) or transporters at clinically relevant plasma concentrations. Empagliflozin is a substrate of uridine diphosphoglucuronosyltransferase (UGT) enzymes (UGT2B7, UGT1A3, UGT1A8, and UGT1A9) and transporters p-glycoprotein (P-gp), breast cancer related protein (BCRP), organic anion transporting polypeptide transporters (OATP1B1, OATP1B3) and organic anion transporter (OAT3). Interaction studies conducted in healthy volunteers suggest that the pharmacokinetics of empagliflozin were not influenced by co-administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide. Increased empagliflozin are under the curve (AUC) was seen following co-administration with gemfibrozil (59%), rifampicin (35%), or probenecid (53%). These changes were not considered to be clinically meaningful.

For further details, please refer to the Jardiance Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Jardiance (empagliflozin) in the treatment of type 2 diabetes mellitus (T2DM) was primarily assessed in four 24-week, pivotal Phase III randomized, multicentre, double-blind, placebo-controlled, parallel-group studies (Studies 1245.20, 1245.23, 1245.23+, and 1245.19). Patients with T2DM and inadequate glycemic control were randomized and treated with Jardiance 10 mg or 25 mg once daily, or placebo.

The studies differed with regards to background medication:

• Study 1245.20 included patients who were not taking any background antidiabetic medication (Jardiance was administered as monotherapy).
• Study 1245.23 included patients taking background medication of metformin only.
• Study 1245.23+ included patients taking background medication of metformin and a sulphonylurea.
• Study 1245.19 included patients with ongoing background medication of pioglitazone with or without metformin.

All four pivotal studies had the same primary efficacy endpoint; the mean change from baseline at Week 24 in hemoglobin A1c (HbA1c). Several secondary endpoints were also examined, including changes in fasting plasma glucose, blood pressure, and body weight. The superiority of both doses of Jardiance over placebo was demonstrated.

Patients who completed one of the pivotal studies could continue in a double-blind extension study, which provided data to support the persistence of efficacy of empagliflozin up to 76 weeks.

Jardiance used as monotherapy (Study 1245.20) or as add-on therapy to metformin (Study 1245.23), to metformin and a sulphonylurea (Study 1245.23+) and to pioglitazone with or without metformin (Study 1245.19) was associated with significant reductions in HbA1c after 24 weeks of treatment.

• Jardiance as monotherapy was associated with a clinically relevant reduction in HbA1c of -0.74% (10 mg) and -0.85% (25 mg), compared to placebo. These reductions were similar to the effect of sitagliptin 100 mg (-0.73%).
• Jardiance as an add-on to metformin was associated with a clinically relevant reduction in HbA1c of -0.57% (10 mg) and -0.64% (25 mg), compared to placebo.
• Jardiance as an add-on to metformin plus a sulfonylurea was associated with a clinically relevant reduction in HbA1c of -0.64% (10 mg) and -0.59% (25 mg), compared to placebo.
• Jardiance as an add-on to pioglitazone (with or without metformin) was associated with a clinically relevant reduction in HbA1c of -0.48% (10 mg) and -0.61% (25 mg), compared to placebo.

The efficacy of Jardiance as an add-on to multiple daily injections of basal and prandial insulin with or without metformin was evaluated in a randomized, double-blind, placebo-controlled study of Jardiance 10 mg and 25 mg, at Week 18 and Week 52 (Study 1245.49). Jardiance demonstrated superiority to placebo treatment in reducing baseline HbA1c. After 18 weeks, the mean placebo-subtracted changes from baseline in HbA1c were -0.44% (10 mg) and -0.52% (25 mg) for Jardiance treatment as add-on to multiple daily injections of basal and prandial insulin alone or with metformin.

In an active-controlled study at 104 weeks, the decrease in HbA1c was statistically significant with Jardiance 25 mg with metformin compared to glimepiride with metformin [-0.66% versus (vs.) -0.55%, (p<0.0001)].

In the pivotal studies, in comparison to placebo, Jardiance was associated with a lower systolic blood pressure (-2.1 to -4.9 mmHg) and a decrease in body weight (1.8 kg for the Jardiance 10 mg group and 2.0 kg for the Jardiance 25 mg group at 24 weeks).

The efficacy and safety of Jardiance as an add-on to antidiabetic therapy were evaluated in patients with T2DM and different degrees of renal impairment in a double-blind, placebo-controlled study for 52 weeks. Although the 10 mg dose is the recommended starting dose of Jardiance, this dose was only studied in patients with mild renal impairment. For patients with T2DM with moderate or severe renal impairment, the 25 mg dose of Jardiance was used. The glucose lowering efficacy of Jardiance 25 mg was reduced in patients with renal impairment [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m²], as expected given its renal mechanism of action. Reduced efficacy was also observed in elderly patients as older patients are more likely to have impaired renal function.

Overall, Jardiance has been shown to be efficacious in the treatment of T2DM, as demonstrated in the pivotal studies. However, despite the efficacy of Jardiance, a Notice of Deficiency (NOD) was issued and the main objection was that the 25 mg tablet strength of Jardiance was proposed as the starting dose for all indications while that the 10 mg dose provided clinically meaningful glycemic efficacy with a good safety profile.

Concerns were raised regarding the sponsor's proposal to market only the 25 mg dose of Jardiance because the available data had shown a numerical advantage of the 10 mg dose. Health Canada observed that the efficacy results for the HbA1c reduction effect had shown significant differences from placebo in favour of Jardiance 10 mg, with confidence intervals overlapping those for the 25 mg dose. It was conceivable that an increased risk of volume depletion and hemoconcentration and/or low density lipoprotein (LDL) elevation with higher doses of Jardiance could offset potentially beneficial cardiovascular effects observed at lower doses, reinforcing the importance of treating patients with the minimal effective dose and attempting dose escalation only if lower doses fail to achieve adequate glycemic control. In the Response to NOD, the sponsor satisfactorily addressed these concerns. The sponsor revised the drug submission to support the use of the 10 mg dose of Jardiance, and as a result Jardiance was considered to have a favourable benefit/risk profile in the treatment of T2DM.

For more information, refer to the Jardiance Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

In the clinical studies, 2,856 patients received treatment with Jardiance 10 mg and 3,738 patients received treatment with Jardiance 25 mg for at least 24 weeks; and 601 patients were treated with Jardiance 10 mg and 881 patients were treated with Jardiance 25 mg for at least 76 weeks. In these studies, the frequency of adverse events (AEs) leading to discontinuation was similar by treatment groups for placebo (5.3%) and Jardiance 10 mg (4.8%) and 25 mg (4.9%).

The most common AEs in patients treated with Jardiance were nausea, urinary tract infection, upper respiratory tract infection, hypoglycemia, dyslipidemia, arthralgia, and vulvovaginal pruritus. The most commonly reported serious AEs across treatment groups were cardiovascular (CV) in nature, consistent with the high CV risk patient population. Adverse events of special interest included decreased renal function, hepatic injury, urinary tract infection, genital infection, hypoglycaemic event, bone fracture, volume depletion, and malignancy.

Jardiance was associated with dose dependent decreases in estimated glomerular filtration rate (eGFR). Jardiance was also associated with increases in creatinine, intravascular volume depletion events (hypotension, syncope, dehydration), genital infections, urinary tract infections, hemoglobin/hematocrit (without evidence of increased thromboembolic events), elevations of hepatic transaminases (greater than five times the upper limit of normal without evidence of drug induced liver injury), mean low-density lipoprotein cholesterol (LDL-C), total cholesterol, and high-density lipoprotein cholesterol (HDL-C).

In a dedicated body composition study, no effects were seen on bone mineral density at either the femoral neck or lumbar spine after 104 weeks of treatment, and no increases in fracture risk were noted in the clinical studies.

Cases of lung cancer and malignant melanoma were reported more frequently in patients treated with Jardiance, however the imbalances were not statistically significant, due to the small numbers of cases, and the apparent imbalances diminished with increased drug exposure. When considered along with the lack of a signal for malignancy in non-clinical studies, a causal relationship to Jardiance is considered unlikely.

During the submission review, post-market cases of diabetic ketoacidosis (DKA) were reported in patients taking SGLT2 inhibitors. In the Jardiance clinical studies, cases of DKA were rare and less common in Jardiance-treated patients than in placebo patients. An Information Update letter regarding this issue was released and Health Canada is currently reviewing the evidence regarding an association with SGLT2 inhibitors.

Risk mitigation includes approval of a risk management plan by Health Canada and labelling of all safety issues identified. These issues include contraindications for use in patients with an eGFR <45 mL/min/1.73m²; warnings against use in patients with evidence of volume depletion, pregnant and nursing women; and use with caution in elderly patients, patients taking antihypertensives, particularly diuretics, patients with a history of low blood pressure, cardiovascular disease, pre-existing elevated hematocrit/hemoglobin level, or severe hepatic or moderate renal impairment. Text was included in the Jardiance Product Monograph warning regarding post-marketing cases of DKA, and describing possible signs, symptoms, and appropriate management. Risk of malignancy, including malignant melanoma, lung, bladder, and breast cancer, and hepatic safety will be monitored as a post-market commitment, through an ongoing cardiovascular outcomes study.

In a prospective meta-analysis of independently adjudicated cardiovascular events from seven Phase II and III clinical studies involving 8,247 patients with T2DM [Number of patients (N) placebo N = 2, 816, empagliflozin 10 mg N = 2, 614, and empagliflozin 25 mg N = 2, 817], empagliflozin did not increase cardiovascular risk as measured by a composite endpoint based on time to first occurrence of CV death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina.

Overall, the safety data supports the market authorization of Jardiance for the specified indication. Appropriate warnings and precautions are in place in the approved Jardiance Product Monograph to address the identified safety concerns.

For more information, refer to the Jardiance Product Monograph, approved by Health Canada and available through the Drug Product Database.