New Diabetes Drug Dapagliflozin (FARXIGA): Risks Outweigh Benefits

Dapagliflozin (FARXIGA) was approved by the Food and Drug Administration (FDA) on Jan. 8, 2014.[1] Patients should not use the drug, however, because it poses serious risks — including the possible risk of cancer — that outweigh its modest benefits.

The drug, jointly marketed in the U.S. by Bristol-Myers Squibb and AstraZeneca, is approved for use (along with diet and exercise) to lower blood glucose levels in patients with Type 2, or non-insulin-dependent, diabetes, the most common type of diabetes in older Americans.[2]

Dapagliflozin is the second member of the newest family of drugs approved to treat Type 2 diabetes. But the fact that a treatment is newer does not mean it is better. Dapagliflozin has not been shown to offer any unique clinical benefits in comparison with several older, safer diabetes drugs. Yet it does pose serious risks. Therefore, Public Citizen’s Health Research Group has categorized the drug as Do Not Use.

How dapagliflozin works

Like its predecessor canagliflozin (INVOKANA), which we also have designated as Do Not Use, dapagliflozin is a sodium-glucose transporter 2 (SGLT2) inhibitor.[3] SGLT2 inhibitors lower blood sugar levels by causing glucose to be excreted by the kidneys into the urine.

When blood initially is filtered by the kidneys, toxic waste products are removed, but so are substances that are essential for life, such as glucose and sodium.

One vitally important function of the kidneys is reabsorbing those substances that are not waste products so they are not lost in the urine. Naturally occurring SGLT2s in the kidneys are responsible for reclaiming most of the filtered glucose and returning it to the blood.

By blocking the function of these transporters, dapagliflozin and other SGLT2 inhibitors prevent some filtered glucose from being reabsorbed by the kidneys, resulting in urinary losses of glucose. As discussed below, many of the important adverse effects of dapagliflozin are a direct result of the drug’s effects on glucose reabsorption by the kidneys.

Limited evidence of benefit

Like so many other drugs approved by the FDA for treating Type 2 diabetes, dapagliflozin was approved based solely on its blood glucose lowering effects — measured by hemoglobin A1c, which reflects how well a patient’s blood sugar has been controlled during the previous two or three months. The drug’s approval was not based on any evidence of improvement in truly important health outcomes.

The drug’s developer, Bristol-Myers Squibb, submitted data from 16 randomized, controlled trials to support dapagliflozin’s effectiveness. In some trials, the drug was compared to a placebo only. In others, it was compared to another diabetic medication, such as metformin (FORTAMET, GLUCOPHAGE, GLUMETZA, RIOMET), plus a placebo.[4] Some studies also compared dapagliflozin alone to dapagliflozin plus another diabetes drug.

The trials demonstrated that the drug only modestly reduced hemoglobin A1c levels when used alone or in combination with other diabetes medications.[5] The drug also was shown to be no better at reducing hemoglobin A1c levels than metformin, an older and safer medication.[6]

What ultimately matters to patients with diabetes, however, is whether the treatment improves survival or reduces diabetic complications, the most important being cardiovascular disease (such as heart attacks and strokes), kidney failure and diabetic retinopathy, which can lead to blindness. None of the randomized controlled trials evaluating dapagliflozin were designed specifically to measure such clinically meaningful outcomes.

Treatment with dapagliflozin was associated with small decreases in body weight and blood pressure.[7] However, there is no evidence from the clinical trials that these effects translated into any improvement in survival or rates of adverse cardiovascular events.

Safety risks

Public Citizen’s Health Research Group testified before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on July 19, 2011, and on Dec. 12, 2013, strongly opposing approval of dapagliflozin because of multiple serious safety concerns and a lack of evidence of any major clinical benefits.[8],[9] Many of these concerns, identified during clinical trials of the drug, apply particularly to the geriatric population.

Possible cancer risk

Data pooled across all clinical trials revealed an increased incidence of bladder cancer in subjects receiving dapagliflozin compared to control group subjects not receiving the drug.[10] While the number of cases was very small and the results did not prove that dapagliflozin causes bladder cancer, an FDA consultant with expertise in cancer risk nevertheless concluded, “Taken together, the current available evidence appears to suggest an increased risk of bladder cancer diagnosis in patients taking dapagliflozin.”[11]

When the FDA rejected Bristol-Myers Squibb’s first application for approval of dapagliflozin on Jan. 17, 2012, the agency concluded that dapagliflozin did not offer a unique benefit that offset that potential risk.[12]

More cases of breast cancer also were diagnosed in women who received dapagliflozin in clinical trials.[13] Again, although the number of cases was very small and the results do not prove dapagliflozin causes breast cancer, they do raise a red flag concerning the safety of a drug that does not represent a major breakthrough in the treatment of diabetes.

Dehydration and impaired kidney function

Dapagliflozin, like canagliflozin, acts like a diuretic because the increased amount of glucose in the urine also causes more water to be lost.[14] This can cause a cascade of adverse events.

Individuals most susceptible to the diuretic effects of dapagliflozin and related complications include patients who have moderately impaired baseline kidney function, those who are age 65 or older, and those who are taking potent loop diuretics (for example, furosemide [LASIX]).[15]

Patients who develop body fluid depletion due to dapagliflozin may experience dry mouth and frequent thirst. They also may be more likely to experience low blood pressure and fainting.[16] Low blood pressure may predispose patients to falls and serious injuries such as hip fractures. Older patients and patients with diabetic neuropathy (nerve damage due to diabetes) are more susceptible to such side effects.

During the randomized clinical trials of the drug, declines in renal (kidney) function also were seen more frequently in subjects exposed to dapagliflozin compared to control subjects who received a placebo.[17] Subjects who were 65 or older or had existing kidney disease were more likely to experience this adverse effect.[18] The declines in renal function occurred within the first week of taking the drug and persisted for months.[19]

Infections

Dapagliflozin was found to cause a significant increase in the incidence of genital fungal infections in both women and men. Among women enrolled in the randomized clinical trials, those receiving dapagliflozin had more than a sevenfold higher incidence of genital fungal infections, such as yeast infections, than those receiving a placebo or another diabetes drug.[20] Men receiving the drug had more than a 17-fold greater incidence of those infections.[21]

Dapagliflozin also was associated with a slight increase in urinary tract infections, which are typically caused by bacteria, in both men and women, compared to subjects who received placebos.[22]

These increases are related to the presence of glucose in the urine, which promotes growth of fungal organisms and bacteria.

What You Can Do

You should avoid taking dapagliflozin if you are not taking it currently.

If you are taking the drug, you should consult your physician about switching to an equally effective and safer drug for Type 2 diabetes, such as metformin or a second- or third-generation sulfonylurea.

Exercise and diet are often instrumental in controlling blood sugar levels.

For more information on treatment options, see the article “Type 2 Diabetes: A Guide to Prevention and Treatment” in the May 2014 issue of Worst Pills, Best Pills News or on WorstPills.org.

References

[1] Food and Drug Administration. NDA approval letter for Farxiga. January 8, 2014. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/202293Orig1s000ltr.pdf. Accessed July 10, 2014.

[2] Bristol-Myers Squibb Co. and AstraZeneca Pharmaceuticals LP. Drug label for FARXIGA (dapagliflozin). March 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s000lbl.pdf. Accessed July 10, 2014.

[3] Ibid.

[4] Food and Drug Administration. FDA briefing document: NDA 202293, dapagliflozin, 5 and 10 mg, sponsor: Bristol-Myes Squibb; Advisory Committee Meeting: December 12, 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf. Accessed July 10, 2013.

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Wolfe S. Testimony before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee regarding dapagliflozin. July 19, 2011. http://www.citizen.org/documents/1957.pdf. Accessed July 10, 2014.

[9] Wolfe S, Almashat S. Testimony before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee regarding dapagliflozin. December 12, 2013. http://www.citizen.org/documents/2173.pdf. July 10, 2014.

[10] Food and Drug Administration. FDA briefing document: NDA 202293, dapagliflozin, 5 and 10 mg, sponsor: Bristol-Myers Squibb; Advisory Committee Meeting: December 12, 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf. Accessed July 10, 2013.

[11] Ibid.

[12] Rosebraugh CJ. The Food and Drug Administration’s complete response letter to Bristol-Myers Squibb regarding the New Drug Application for dapagliflozin. January 17, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378077.pdf. Accessed July 10, 2014.

[13] Food and Drug Administration. FDA briefing document: NDA 202293, dapagliflozin, 5 and 10 mg, sponsor: Bristol-Myers Squibb; Advisory Committee Meeting: December 12, 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf. Accessed July 10, 2013.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] Ibid.

[19] Pucino F. Food and Drug Administration clinical review for the New Drug Application for dapagliflozin. December 22, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf. Accessed July 10, 2014.

[20] Food and Drug Administration. FDA briefing document: NDA 202293, dapagliflozin, 5 and 10 mg, sponsor: Bristol-Myers Squibb; Advisory Committee Meeting: December 12, 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf. Accessed July 10, 2013.

[21] Ibid.

[22] Ibid.