Risks but No Benefits to Taking Newest Drugs For Type 2 Diabetes

Canagliflozin (INVOKANA), dapagliflozin (FARXIGA) and empagliflozin (JARDIANCE) belong to the newest class of drugs approved for the treatment of Type 2 diabetes.[1] These drugs, sodium-glucose transporter 2 (SGLT2) inhibitors, change the way the kidneys work: They lower blood sugar levels by causing glucose to be excreted by the kidneys into the urine. This new class of drugs is often referred to as "flozins." Despite these multiple approvals in less than a two-year period, none of the flozin drugs have any proven impact on improving health outcomes in patients with Type 2 diabetes.

Public Citizen's Health Research Group does not recommend the use of flozins, not only because they do not offer any clinical benefits in comparison with several older, safer diabetes drugs, but also because they are associated with unique, serious risks compared to these safer drugs.

Beyond the very minimal benefits in controlling blood sugar, there is no evidence from clinical trials that flozins improve survival or reduce long-term, life-threatening diabetic complications. Clinical trial data submitted to the Food and Drug Administration (FDA) indicates that flozins actually may increase the risk for cardiovascular disease (heart attack and stroke) and kidney failure.

Flozins are associated with a significant increase in LDL, or "bad," cholesterol (by 4 percent with dapagliflozin and 12 percent with canagliflozin),[2],[3],[4] and increases in red blood cell levels,[5],[6],[7] which are both known risk factors for increased cardiovascular disease. Members of the FDA advisory committee reviewing the risk-benefit profiles for canagliflozin[8] and dapagliflozin[9] expressed concern about cardiovascular risks and indicated the necessity for long-term cardiovascular safety studies.

Flozins are associated with worsening kidney function, especially in older adults. For example, older diabetic patients with moderate kidney impairment are more likely to experience a decline in kidney function when using dapagliflozin (23.7 percent) than when using a placebo (10.8 percent).[10] This poses a very serious safety concern, since a key goal of diabetes management is the prevention of kidney impairment.

Diuretic effects and falls

The diuretic effect of flozins — water loss due to the increase in the amount of glucose in the urine — causes body fluid depletion and is responsible for a series of additional, potentially serious, adverse effects associated with dehydration, particularly hypotension (low blood pressure).[11],[12],[13] Low blood pressure can predispose patients to falls, the leading cause of fatal and nonfatal injuries in older adults. [14]

Not surprisingly, risk of bone fractures associated with falls in patients using flozins also has been identified as a serious safety concern.[15] FDA medical reviews of dapagliflozin's safety profile indicate a twofold increase in the incidence of fractures and suggest that these fractures likely were related to falls.[16] No increased fracture risk was identified during clinical testing of empagliflozin.[17]

Canagliflozin and dapagliflozins can be even more dangerous when combined with certain widely used medications.[18],[19] Angiotensin converting enzyme inhibitors such as lisinopril (PRINIVIL, ZESTRIL) and angiotensin II receptor blockers such as losartan (COZAAR), two common types of blood pressure medications, often are prescribed and used in diabetic patients to prevent kidney disease. But when they are combined with flozins, there is evidence of a more than twofold increased incidence of kidney problems.[20]

Infections

Because it promotes growth of fungal organisms and bacteria, the increased amount of sugar in the urine also can cause a significant increase in bothersome and recurrent genital and urinary tract infections.[21],[22] Compared to women using a placebo, the rate of genital fungal infections, such as yeast infections, for women using dapagliflozin was more than seven times higher (8.4 percent versus 1.2 percent for those using a placebo). The incidence of penile infections in men using dapagliflozin was 17 times higher than in those getting a placebo (3.4 percent vs. 0.2 percent).[23]

Cancer risk

The flozin drugs also come with additional drug-specific risks, including cancer. When the FDA rejected Bristol-Myers Squibb's initial application for approval of dapagliflozin on Jan. 17, 2012, the agency concluded that dapagliflozin did not offer a strong enough benefit to offset the potential risks.[24] Specifically, women taking dapagliflozin were two times more likely to be diagnosed with breast cancer, and men taking the drug were five times more likely to be diagnosed with bladder cancer.[25]

Despite persistent clinical evidence of these cancer risks more than two years later, the FDA approved dapagliflozin in January 2014.[26] However, the agency did require postmarketing studies to be conducted on the drug, as well as requiring the product label to warn about the risk of bladder cancer.[27]

The highly regarded French drug safety bulletin Prescrire International also considers these drugs "not acceptable" and dangerous. In addition, FDA documents suggest that empagliflozin may be associated with increased incidences of both lung and skin cancers (melanoma), although FDA reviewers felt the number of cases was too small to draw firm conclusions.[28]

Clinical trials generally do not enroll enough subjects to detect rare cancer risks. Since, despite this, higher rates of several different types of cancer appeared during clinical testing, the concern is raised that additional cancer risks may have gone undetected.

What You Can Do

Due to very limited clinical benefits and a series of serious safety concerns, we recommend that you do not use any of the flozin drugs.

Our first recommendation for treating Type 2 diabetes is diet and exercise. If these are insufficient, we recommend use of metformin (FORTAMET, GLUCOPHAGE, GLUMETZA, RIOMET) or drugs known as second- or third-generation sulfonylureas such as glyburide (DIABETA, GLYNASE) and glimepiride (AMARYL). For more detailed recommendations, please visit www.WorstPills.org or see the May 2014 issue of Worst Pills, Best Pills News.

References

[1] Singh S. Type 2 diabetes pharmacoepidemiology update 2014: Safety versus efficacy. Curr Diab Rep. 2014;14: 563. DOI 10.1007/s11892-014-0563-4

[2] Boehringer Ingelheim Pharmaeuticals. Drug label for JARDIANCE (empagliflozin) tablets. August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf

[3] Food and Drug Administration. FDA briefing document: NDA 20402, canaglifozin, sponsor: Janssen Pharmaceuticals; Advisory Committee meeting. January 10, 2013 (p. 91). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrug sAdvisoryCommittee/UCM334550.pdf.

[4] Food and Drug Administration. FDA briefing document: NDA 202293, dapaglifozin, sponsor: Bristol-Myers Squibb; Advisory Committee meeting. December 12, 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf.

[5] Boehringer Ingelheim Pharmaeuticals. Drug label for JARDIANCE (empagliflozin) tablets. August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf.

[6] Food and Drug Administration. FDA briefing document: NDA 20402, canaglifozin, sponsor: Janssen Pharmaceuticals; Advisory Committee meeting. January 10, 2013 (p. 68). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334550.pdf.

[7] Food and Drug Administration. FDA briefing document: NDA 202293, dapaglifozin, sponsor: Bristol-Myers Squibb; Advisory Committee meeting. December 12, 2013 (p. 64). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf.

[8] Parks M. Food and Drug Administration summary review for canagliflozin (INVOKANA) tablets (p. 26). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000SumR.pdf.

[9] Guettier J. Food and Drug Administration summary review for dapagliflozin (FARXIGA) tablets (p. 18). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000SumR.pdf.

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

[11] Boehringer Ingelheim Pharmaeuticals. Drug label for JARDIANCE (empagliflozin) tablets. August 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf.

[12] Food and Drug Administration. FDA briefing document: NDA 202293, dapaglifozin, sponsor: Bristol-Myers Squibb; Advisory Committee meeting, December 12, 2013 (p 64). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf.

[13] Food and Drug Administration. FDA briefing document: NDA 20402, canaglifozin, sponsor: Janssen Pharmaceuticals; Advisory Committee meeting. January 10, 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334550.pdf.

[14] Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Falls Among Older Adults: An Overview. http://www.cdc.gov/HomeandRecreationalSafety/Falls/adultfalls.html.

[15] Prescrire editorial staff. Dapagliflozin. A hypoglycemic drug causing disproportionate harm, especially to the kidneys. Prescrire International. 2014;23(147):61-64.

[16] Whitaker M. Food and Drug Administration medical review of dapagliflozin bone effects. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000OtherR.pdf.

[17] Mahoney K. Food and Drug Administration cross-disciplinary review of empaglifozin. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000MedR.pdf.

[18] Prescrire editorial staff. Canagliflozin. A "me too" of the dangerous dapagliflozin. Prescrire International. 2015;24(157):33-35.

[19] Prescrire editorial staff. Dapagliflozin. A hypoglycemic drug causing disproportionate harm, especially to the kidneys. Prescrire International. 2014;23(147):61-64.

[20] Kwon H. Food and Drug Administration clinical review for canagliflozin (INVOKANA) tablets. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf.

[21] Prescrire editorial staff. Dapagliflozin. A hypoglycemic drug causing disproportionate harm, especially to the kidneys. Prescrire International. 2014;23(147):61-64.

[22] Prescrire editorial staff. Canagliflozin. A "me too" of the dangerous dapagliflozin. Prescrire International. 2015;24(157):33-35.

[23] Food and Drug Administration. FDA briefing document: NDA 202293, dapaglifozin, sponsor: Bristol-Myers Squibb; Advisory Committee meeting. December 12, 2013 (p. 51). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf.

[24] Pucino F. Food and Drug Administration clinical review for dapagliflozin (FARXIGA) tablets http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf.

[25] Dunn S. Food and Drug Administration clinical review for new drug application for dapagliflozin. September 2,2011 (p. 299). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf.

[26] Food and Drug Administration. NDA approval letter for dapagliflozin (FARXIGA) tablets. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/202293Orig1s000ltr.pdf.

[27] Guettier J. Food and Drug Administration summary review for dapagliflozin (FARXIGA) tablets. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000SumR.pdf.

[28] Chong W. Food and Drug Administration medical review for empagliflozin (JARDIANCE) tablets. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000MedR.pdf.