Pharmacology Update
Dapagliflozin Tablets (Farxiga)
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 second sodium-glucose cotransporter 2 (sglt2) inhibitor has been approved for the treatment of adults with type 2 diabetes mellitus. These agents increase glucose secretion by inhibiting reabsorption in the kidney. Renal glucose threshold can be lowered to 70-90 mg/dL from a norm of 240 mg/dL in patients with diabetes. Dapagliflozin follows canagliflozin as the second SGLT2 approved and is marketed by Bristol-Myers Squibb and AstraZeneca as Farxiga.
Indications
Dapagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1 It may be used as monotherapy or in combination with other type 2 diabetes medications.
Dosage
The recommended dose is 5 mg once daily taken in the morning, without regard to meals. The dose may be increased to 10 mg daily. Dapagliflozin should not be initiated in patients with eGFR < 60 mL/min/1.73 m2 and should be discontinued if eGFR is consistently below this value.1 Dapagliflozin is available as 5 mg and 10 mg tablets.
Potential Advantages
Dapagliflozin has greater selectivity for SGLT2 selectivity than canagliflozin and is more potent on an mg for mg basis.2
Potential Disadvantages
Adverse reactions include reduction in intravascular volume and hypotension. The drug should be avoided in the elderly and others prone to hypotension or orthostasis. Other adverse events include increased serum creatinine, decrease in eGFR, increases in low-density lipoprotein cholesterol (LDL-C), genital mycotic infections, and hypoglycemia if used with insulin or insulin secretagogues. There was a higher frequency of bladder cancer reported (10/6045) compared to control (1/3512).1 No increased risk has been reported with canagliflozin.2 SGLT2 selectivity may also be a disadvantage, as canagliflozin transiently inhibits intestinal SGLT1, which results in delaying intestinal glucose absorption resulting in reduced postprandial plasma glucose and insulin excursion.3
Comments
The efficacy of dapagliflozin have been evaluated in numerous studies as monotherapy and in combination with metformin, insulin, and pioglitazone as well as add on therapy.1,2,4,5 Primary efficacy endpoints were change in HbA1c and fasting plasma glucose (FPG). For an overview of the efficacy of dapagliflozin, the FDA reviewer pooled the data from the phase 3 placebo-controlled data with the endpoint of 24 weeks (n = 2274).4 Mean baseline HbA1c ranged from 8.2-8.4% and FPG ranged from 166-175 mg/dL. The adjusted change in HbA1c was -0.5% for both the 5 mg (95% confidence interval [CI], -0.58 to -0.43) and 10 mg doses (95% CI, -0.58 to -0.47). Changes in FPG were -22 mg/dL (95% CI, -25 to -19) for the 5 mg dose and -25 mg/dL (95% CI, -27 to -22) for the 10 mg dose. Loss in body weight was -1.40 kg and -1.82 kg for the two strengths. Systolic blood pressure was reduced by -2.28 mmHg and -3.17 mmHg. LDL-C increased by 2.47 mg/dL and 3.34 mg/dL. The addition of dapagliflozin to metformin achieved -0.4% reduction with 5 mg and -0.5% for the 10 mg dose. At 54 weeks, the addition of dapagliflozin (up to 10 mg daily) to metformin was noninferior to glipizide (up to 20 mg/day) added to metformin.1 The addition of dapagliflozin to various classes of antidiabetes drugs achieved an adjusted reduction of HbA1c of -0.4% to -0.7%.1 Dapagliflozin does not appear to affect markers of bone turnover or bone mineral density.6 Genital and urinary tract infections were higher with dapagliflozin compared to placebo (7.4-14.3% vs 3% and 8.4-13.8% vs 5.6%).7 Most of these occurred in the first 24 weeks.
Clinical Implications
Dapagliflozin is the second and more potent SGLT2 inhibitor approved by the FDA. The long-term effect of dapagliflozin remains to be determined. The numerical imbalance in bladder cancers associated with the drug has raised concerns. Findings from various non-clinical studies suggest that dapagliflozin is not a direct tumor promoter or inducer and the effect may be secondary to changes in the microenvironment within the bladder.4 The wholesale cost is $289 for a 30-day supply for either strength.
References
- Farxiga Prescribing Information. New York, NY: Bristol-Myers Squibb. January 2014.
- Riser TS, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy 2013;33:984-999.
- Polidori D, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study. Diabetes Care 2013;36:2154-2161.
- http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf. Accessed February 10, 2014.
- Ferrannini E, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: A randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-2224.
- Bolinder J, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 2013; Aug 1. [Epub ahead of print.]
- Wilding JP, et al. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab 2013; Aug 1. [Epub ahead of print.]
