PHARMACOLOGY UPDATE
Empagliflozin Tablets (Jardiance ®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A new sodium glucose co-transporter 2 (SGLT2)
has been approved by the FDA. Empagliflozin follows canagliflozin (Invokana) and dapagliflozin (Farxiga)as the third entry in this group. These drugs reduce plasma glucose levels by reducing renal absorption of filtered glucose. Empagliflozin is marketed by Boehringer Ingelheim as Jardiance.
INDICATION
Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1
DOSAGE
The recommended dose is 10 mg once daily in the morning.1 It may be taken without regard to meals. The dose may be increased to 25 mg. The drug should not be initiated if eGFR is below 45 mL/min/1.73 m2 and it should be discontinued if the eGFR falls below 45 mL/min/1.73 m2.
POTENTIAL ADVANTAGES
Empagliflozin does not appear to have any important clinical interactions with CYP450 isoforms, UGT1A1, P-glycoprotein and breast cancer resistant protein (BCRP), and human uptake transporters.1 Empagliflozin may be used in patients with hepatic impairment.1
POTENTIAL DISADVANTAGES
As a class, the SGLT2 inhibitors cause intravascular volume contraction. Symptomatic hypotension may occur particularly in the elderly, those with renal impairment, those with low systolic blood pressure, and those on diuretics.1
COMMENTS
Empagliflozin was studied as monotherapy as well as in combination with metformin, sulfonylurea, pioglitazone, and insulin.1 In the monotherapy study, subjects with type 2 diabetes (n = 676) with an HbA1c between 7-10% were randomized to empagliflozin 10 mg, 25 mg, or placebo. At week 24, empagliflozin showed a difference from placebo of 0.7% (97.5% confidence interval [CI], -0.9 to -0.6) for 10 mg and -0.9% (97.5% CI, -1.0 to -0.7) for 25 mg. Fasting plasma glucose showed a difference from placebo of -31 mg/mL (95% CI, -37 to -26), and -36 mg/mL (95% CI, -42 to -31), respectively. There was a significant loss in body weight of 2.5-2.8 kg with the drug. Systolic blood pressure was significantly reduced by 2.6 mmHg relative to placebo. The addition of empagliflozin to metformin, metformin plus sulfonylurea, pioglitazone, or insulin showed a HbA1c difference from placebo of about -0.6% in previously inadequately controlled diabetics. In a 52-week study, there was no significant difference in reduction of HbA1c between empagliflozin or glimepiride when added to metformin in previously inadequately controlled subjects. The most common adverse events were urinary tract infections (7-9% vs 7.6% for placebo) and female genital mycotic infections (5.4-6.4% vs 1.5% for placebo).
CLINICAL IMPLICATIONS
Empagliflozin is the third SGLT2 inhibitor to come on the market. These drugs provide a new mechanism of action to improve glycemic control with modest decreases in systolic blood pressure and body weight. There are no published comparative studies among the three agents. An indirect comparison of monotherapy studies suggests that the magnitude of effect (reduction in HbA1c and fasting glucose) may be similar to dapagliflozin but numerically less than canagliflozin.2,3 This may be related to the additional inhibition of SGLT1 with canagliflozin, delaying intestinal glucose absorption.4 Dapagliflozin has been linked to possible bladder cancer risk. Canagliflozin is not recommended in patients with severe hepatic impairment. Empagliflozin is being evaluated in an international study in type 2 diabetics with high cardiovascular risk for long-term cardiovascular safety as well as potential benefits on macro-/microvascular outcomes with results expected in 2015.5 Empagliflozin has the lowest wholesale cost at $301 per 30-day supply compared to $312 for dapagliflozin and $374 for canagliflozin.
REFERENCES
- Jardiance Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; August 2014.
- Invokana Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals, Inc.; May 2014.
- Farxiga Prescribing Information. New York City, NY: Bristol-Myers Squibb; August 2014.
- Polidori D, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion. Diabetes Care 2013; 36:2154-2161.
- Zinman B, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin. Cardiovasc Diabetol 2014;13:102.
