Drugs in Perspective: Farxiga (dapagliflozin)

Antidiabetic drugs are considered to be first-line treatment options for individuals with type 1 and type 2 diabetes mellitus. It is estimated that type 2 diabetes affects about 24 million persons in the United States. Over time high blood levels can lead to complications such as heart disease, kidney damage, or blindness.¹ When it comes to the treatment of type 2 diabetes individuals have the option of using oral hypoglycemic agents, compared to individuals with type 1 diabetes that requires insulin therapy.

Farxiga (dapagliflozin), in tablets for oral use, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that was approved by FDA in January 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.² As a SGLT2 inhibitor, it works in the proximal renal tubules and decreases the glucose reabsorption and increased glucose excretion.^3,4 It is available as a 5-mg and 10-mg oral tablet.³ The suggested dosing regimen is 5 mg once daily in the morning, with or without food, with an increase to 10 mg once daily. For individuals with renal impairment, use is to be avoided in those with an estimated glomerular filtration rate (eGFR) of 30 to 59 and use is contraindicated in those with an eGFR less than 30.

Relevance

Although there are many other antidiabetic drugs on the market dapagliflozin is unique in the novel approach that it takes to reduce blood sugar by blocking reabsorption of glucose by the kidneys, increasing the excretion of glucose in the urine, and reducing the glucose levels in the blood.⁵ It tends to differ from other drugs that decrease the amount of sugar that is absorbed from food and ultimately stored in the liver. It is the second drug of its kind, following canagliflozin, which was approved in March 2013.⁶

Studies

FDA approval was based on both monotherapy and combination clinical studies. The combination studies involved metformin, pioglitazone, glimepiride, sitagliptin (with or without metformin), or insulin (with or without other oral antidiabetic therapy).⁷ The monotherapy trial consisted of a total of 840 treatment-naïve patients with inappropriately controlled type 2 diabetes who participated in 2 placebo-controlled studies to assess the safety and efficacy of dapagliflozin.^7,8 One of the studies was a 24-week study that included 558 subjects on a 2-week diet and exercise placebo lead-in period, 485 subjects with hemoglobin (Hb)A_1c greater than 7%, and less than 10% randomized to dapagliflozin 5 mg or 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo. It was at 24 weeks that the treatment with dapagliflozin 10 mg QAM provided significant improvements in HbA_1c and fasting plasma glucose (FPG) compared with placebo. The study’s findings demonstrated a change from baseline in HbA1c for dapagliflozin: -0.9 versus placebo: -0.2; change from baseline in FPG for dapagliflozin: -28.8 versus placebo: -4.8.

The combination therapy studies consisted of 1,241 treatment-naïve participants with inadequately controlled type 2 diabetes (HbA1c ≥7.5% and ≤12%) in 2 active controlled studies for 24 weeks to assess the safety and efficacy of therapy with dapagliflozin 5 mg or 10 mg in combination with metformin extended release. The combination of dapagliflozin 10 mg plus metformin extended release demonstrated statistically significant improvement in HbA_1c and FPG compared to monotherapy treatment. The result of dapagliflozin 10 mg as add-on treatment to metformin also demonstrated statistically significant improvement in HbA1c and FPG. Dapagliflozin also demonstrated mean reduction in HbA_1c from baseline at week 52 (LOCF), compared with glipizide, and dapagliflozin treatment led to a statistically significant mean reduction in body weight from baseline at week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Dapagliflozin 10 mg  also displayed statistically significant improvement in HbA_1c, FPG, and 2-hour postprandial glucose (PPG), and statistically significant reduction in body weight compared with placebo plus glimepiride at week 24.⁷ When used in combination with pioglitazone, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA_1c, 2-hour PPG, FPG, the proportion of patients achieving HbA_1c less than 7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups. When used in combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided statistically significant improvements in HbA_1c, FPG, and a statistically significant reduction in body weight compared with placebo plus sitagliptin (with or without metformin) group at week 24.^7,8 At week 24, when it was combined with insulin, dapagliflozin 10 mg dose demonstrated statistically significant improvement in HbA_1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 oral antidiabetics (OADs); the effect of dapagliflozin on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD.^7,8

Potential advantages and disadvantages

The drug was originally rejected in 2012 after advisers raised concerns related to bladder and breast cancer risk. There were additional studies performed that helped to reduce the concern, and it was later supported by advisers in December 2013. The approval of dapagliflozin is big news for many with type 2 diabetes because it offers a new approach to targeting the management of diabetes. Nevertheless, because it is a new drug the breadth of the information with regard to safety and effectiveness is not the same as that available for older agents. Additionally, there are concerns over the increased risk of bladder and breast cancer; FDA has ordered postmarketing trials to be conducted by Bristol-Myers Squibb and AstraZeneca to explore its effects on the flow of urine and tumor growth. FDA requests 6 additional postmarketing studies to assess cardiovascular risk in those at high risk for cardiovascular disease, assessment of bladder cancer in patients, an animal study of urinary flow and rate of bladder tumor growth, 2 studies to evaluate use in pediatric patients, and a program to monitor reports of liver problems and its effects on pregnancy.⁹

Cost

Although dapagliflozin was approved in early 2014, the anticipated availability of the drug is still unknown as well as the posted price of the drug (www.drugstore.com). It will only be available in brand; the generic version will not be available.

Place in therapy

The approval and subsequent availability of dapagliflozin will provide another oral antidiabetic agent to patients diagnosed with type 2 diabetes. Historically, the treatment of type 2 diabetes requires multiple drugs with different mechanisms of action to effectively control blood sugars, but dapagliflozin is distinct in the fact that it seeks to block reabsorbable glucose levels in the kidney while also increasing the excretion of glucose in the urine.¹⁰

Implications

FDA approval of dapagliflozin has significant implications for diabetes management, monitoring, and the future direction of treatment. As it currently stands, there are concerns of associated cancer risk with the use of dapagliflozin, which is still subject to postmarketing trials, but it provides another option for the millions diagnosed with type 2 diabetes. For patients who are not able to get their HbA_1c to goal and would like the opportunity to try another agent, dapagliflozin may be viewed as an alternative choice. Prior to initiating therapy it is important for pharmacists to reiterate the importance of patients discussing current medication and all medication changes with their provider to determine whether dapagliflozin is an option for them.

Dr Farinde serves on the faculty at Columbia Southern University, Orange Beach, Ala. 

Disclosure information: The author reports no financial disclosures as related to products discussed in this article.

References

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War on diabetes. Farxiga (Forxiga) approved for use in the United States. http://www.warondiabetes.org/2014/01/08/farxiga-forxiga-approved-for-use-in-the-united-states/. Accessed February 27, 2014.

Lees K. New medication for diabetes approved by FDA. Science World Report. http://www.scienceworldreport.com/articles/12085/20140109/new-medication-for-diabetes-approved-by-fda.htm. Accessed February 27, 2014.