Public Citizen Calls on FDA to Require Black-Box Warning for Newest Diabetes Drugs

On June 24, 2020, Public Citizen petitioned the Food and Drug Administration (FDA) to add a black-box warning — the strongest warning that the agency can require — to the product labeling for the commonly used type 2 diabetes drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors, as they can lead to potentially fatal diabetic ketoacidosis in type 1 diabetes mellitus (diabetes) patients.[1]

SGLT2 inhibitors, often referred to as “flozins” or “gliflozins,” are the newest class of drugs approved only for the treatment of type 2 diabetes. However, some doctors have prescribed them to patients with type 1 diabetes, a so-called “off-label” use. Four SGLT2 inhibitors are available in the U.S. (see Table, below). They lower blood sugar levels by causing glucose to be excreted by the kidneys into the urine.

FDA-Approved SGLT2 Inhibitors

†Combination drug product that contains one or more other diabetes drugs

Public Citizen’s Health Research Group for several years has recommended against the use of SGLT2 inhibitors for type 2 diabetes, not only because they do not offer any unique clinical benefits in comparison with several older, safer diabetes drugs, but also because they are associated with unique, serious risks compared with these safer drugs. As we explained in our petition to the FDA, patients with type 1 diabetes in particular must never use these drugs.

Diabetes overview

Diabetes is a malfunction of the body’s system for regulating glucose (sugar) through the production and use of insulin. When the body does not produce enough insulin, or when cells in muscles and other body tissues fail to respond normally to insulin, sugar is not removed from the bloodstream, causing high levels to accumulate.

Type 1 diabetes occurs in less than 10% of Americans diagnosed with diabetes. These patients do not produce any natural insulin because the cells in the pancreas that make the hormone have been destroyed by the immune system. Type 1 diabetes patients require insulin injections to survive. A common complication of type 1 diabetes is diabetic ketoacidosis, a condition caused by the body burning fat for energy due to insufficient insulin, which can lead to the rapid accumulation of ketones, a type of acid, in the blood.

About 90% of patients with diabetes have type 2 diabetes. Patients with this condition still produce natural insulin, but cells in their muscles and other tissues do not respond normally to the hormone (so-called “insulin resistance”). Most patients with type 2 diabetes are overweight or obese. If they cannot control their diabetes with weight reduction and exercise, most use one of the older oral diabetes drugs. A much smaller number also use insulin in order to control blood sugar.

Current inadequate warnings

The original and current product labeling for all four SGLT2 inhibitors includes the following weak statement: “Limitation of Use: [This drug] is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.”[2],[3],[4],[5]

In 2015, the FDA issued two safety alerts about the risk of ketoacidosis to the product labeling for the three then-approved SGLT2 inhibitors: canagliflozin, dapagliflozin and empagliflozin.[6],[7] The alert was based on the agency’s analysis of 73 reported cases of ketoacidosis associated with use of the SGLT2 inhibitors, all of which required hospitalization or emergency room treatment. These findings prompted the FDA to revise the product labeling for all SGLT2 inhibitors to include a new warning about the risk of “serious life-threatening” drug-induced ketoacidosis in both type 1 and type 2 diabetes patients.[8],[9],[10] In 2016, this warning was modified to state that “Fatal cases of ketoacidosis have been reported in patients taking” SGLT2 inhibitors.[11],[12],[13] The warning has undergone additional minor changes since 2016 but still lacks an explicit directive (known as a contraindication) against using these drugs to treat type 1 diabetes patients.

Definitive evidence of harm

Results from a total of eight large randomized, placebo-controlled clinical trials that each evaluated one of the FDA-approved SGLT2 inhibitors or sotagliflozin (a similar drug known as a dual SGLT1/SGLT2 inhibitor, which was rejected by the FDA) as add-on therapy to insulin for patients with type 1 diabetes have been published in peer-reviewed scientific journals. Canagliflozin was tested in one such trial,[14] dapagliflozin in two,[15],[16] empagliflozin in two[17] and sotagliflozin in three.[18],[19],[20] The duration of the trials ranged from 18 to 52 weeks.

All studies showed a much greater incidence of diabetic ketoacidosis in subjects randomized to receive canagliflozin, dapagliflozin, empagliflozin or sotagliflozin than subjects randomized to receive a placebo. The collective number of subjects with type 1 diabetes who developed diabetic ketoacidosis in these eight clinical trials was 141 (3.3%) of 4,317 subjects randomized to receive one of three FDA-approved SGLT2 inhibitors or sotagliflozin and only 16 (0.7%) of 2,362 subjects randomized to receive a placebo. A published analysis of data from these eight trials — plus two unpublished small clinical trials that tested sotagliflozin — found that the risk of diabetic ketoacidosis in subjects receiving canagliflozin, dapagliflozin, empagliflozin or sotagliflozin was three times higher than the risk for placebo-group subjects.[21]

These same eight published clinical trials also found that the improvements in HbA1c level, which is routinely used to assess the adequacy of blood sugar control in diabetes patients, were small within the first 24 weeks of taking the drug. Moreover, these clinical trials showed a consistent and progressive loss of the previously achieved HbA1c improvement between 24 and 52 weeks.[22]

Because of these findings, the manufacturer of canagliflozin apparently never sought FDA approval of the drug for treating patients with type 1 diabetes. The manufacturers of dapagliflozin, empagliflozin and sotagliflozin each applied to the FDA for approval for such use of their drugs, but in each case the FDA rejected the application largely because of concerns that the risk of harm from diabetic ketoacidosis outweighed the benefits of the drug for type 1 diabetes patients.[23],[24],[25]

Finally, through the end of 2019, the FDA had received 550 reports of diabetic ketoacidosis associated with the use of SGLT2 inhibitors in patients with type 1 diabetes. A total of 374 of these cases were reported to the FDA following the FDA-mandated addition of the new warning about the risk of ketoacidosis to the product labeling for all FDA-approved SGLT2 inhibitors in December 2015. Among the 550 cases reported to the FDA, the diabetic ketoacidosis adverse events resulted in hospitalization in 411 cases and were characterized as life-threatening in 68 cases.

Requested action

Given the irrefutable evidence that SGLT2 inhibitors significantly increase the risk of life-threatening diabetic ketoacidosis in patients with type 1 diabetes, Public Citizen’s petition urged the FDA to immediately require the addition of a black-box warning about this risk to the product labeling for all these drugs.

We proposed that this warning include a “contraindication” statement for type 1 diabetes patients, which means the drug must never be prescribed to such patients. We also asked that the product labeling be revised to include a brief summary of the strong evidence for this contraindication. At press time, FDA action on our petition was pending.
 

References

[1] Public Citizen. Citizen petition to the Food and Drug Administration to require a boxed warning for all sodium-glucose cotransporter-2 (SGLT2) inhibitor drugs contraindicating their use in patients with type 1 diabetes mellitus. June 24, 2020. https://www.citizen.org/wp-content/uploads/2529.pdf. Accessed July 23, 2020.

[2] Janssen Pharmaceutical Companies. Label: canagliflozin (INVOKANA). January 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204042s036lbl.pdf. Accessed July 23, 2020.

[3] AstraZeneca Pharmaceuticals. Label: dapagliflozin (FARXIGA). January 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202293s021lbl.pdf. Accessed July 23, 2020.

[4] Boehringer Ingelheim Pharmaceuticals. Label: empagliflozin (JARDIANCE). January 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204629s023lbl.pdf. Accessed July 23, 2020.

[5] Merck Sharp & Dohme Corp. Label: ertugliflozin (STEGLATRO). January 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209803s002lbl.pdf. Accessed July 23, 2020.

[6] Food and Drug Administration. Drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. May 15, 2015. https://www.fda.gov/media/92185/download. Accessed July 23, 2020.

[7] Food and Drug Administration. Drug safety communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. December 4, 2015. https://www.fda.gov/media/94822/download. Accessed July 23, 2020.

[8] Janssen Pharmaceutical Companies. Label: canagliflozin (INVOKANA). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204042s013lbl.pdf. Accessed July 23, 2020.

[9] AstraZeneca Pharmaceuticals. Label: dapagliflozin (FARXIGA). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202293s008lbl.pdf. Accessed July 23, 2020.

[10] Boehringer Ingelheim Pharmaceuticals. Label: empagliflozin (JARDIANCE). December 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204629s007lbl.pdf. Accessed July 23, 2020.

[11] Janssen Pharmaceutical Companies. Label: canagliflozin (INVOKANA). August 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s022lbl.pdf. Accessed July 23, 2020.

[12] AstraZeneca Pharmaceuticals. Label: dapagliflozin (FARXIGA). August 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202293s010lbl.pdf. Accessed July 23, 2020.

[13] Boehringer Ingelheim Pharmaceuticals. Label: empagliflozin (JARDIANCE). December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s008lbl.pdf. Accessed July 23, 2020.

[14] Henry RR, Thakkar P, Tong C, et al. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38(12):2258-2265.

[15] Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care. 2018;41(12):2552-2559.

[16] Mathieu C, Dandona P, Gillard P, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial. Diabetes Care. 2018;41(9):1938-1946.

[17] Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: The EASE trials. Diabetes Care. 2018;41(12):2560-2569.

[18] Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: The North American inTandem1 study. Diabetes Care. 2018;41(9):1970-1980.

[19] Danne T, Cariou B, Banks P, et al. HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 study. Diabetes Care. 2018;41(9): 1981-1990.

[20] Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017;377(24):2337-2348.

[21] Lu J, Tang L, Meng H, et al. Effects of sodium-glucose cotransporter (SGLT) inhibitors in addition to insulin therapy on glucose control and safety outcomes in adults with type 1 diabetes: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2019;35:e3169.

[22] Taylor SI, Blau JE, Rother KI, Beitelshees AL. SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: Balancing benefits and risks. Lancet Diabetes Endocrinol. 2019;7(12):949-958.

[23] AstraZeneca. Update on US regulatory decision for Farxiga in type-1 diabetes. July 15, 2019. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2019/update-on-us-regulatory-decision-for-farxiga-in-type-1-diabetes-15072019.html. Accessed July 23, 2020.

[24] Boehringer Ingelheim. US FDA issues complete response letter for empagliflozin 2.5 mg as adjunct to insulin for adults with type 1 diabetes. March 20, 2020. https://www.boehringer-ingelheim.us/press-release/us-fda-issues-complete-response-letter-empagliflozin-25-mg-adjunct-insulin-adults-type. Accessed July 23, 2020.

[25] Tucker ME. FDA turns down sotagliflozin for type 1 diabetes. March 22, 2019. https://www.medscape.com/viewarticle/910851. Accessed July 23, 2020.