Incretin-Mimetic Drugs: Do Not Use to Treat Diabetes

Albiglutide (TANZEUM), dulaglutide (TRULICITY), exenatide (BYDUREON, BYETTA) and liraglutide (VICTOZA) are members of a newer class of drugs approved by the Food and Drug Administration (FDA) for the treatment of Type 2 diabetes. These drugs are commonly referred to as incretin-mimetic drugs.

Despite millions of prescriptions sold for these costly drugs each year in the U.S., there is no conclusive evidence that incretin-mimetic drugs improve health outcomes in patients with Type 2 diabetes. Public Citizen’s Health Research Group lists all incretin mimetics as Do Not Use.

Incretin mimetics

Incretin mimetics work by mimicking the effect of a naturally occurring hormone called glucagon-like peptide-1 — also known as incretin — that is present on the surface of many organs, including the intestines, pancreas and thyroid. In the pancreas, incretin stimulates the release of insulin, which, in turn, lowers blood sugar. Since incretin-mimetic drugs would be destroyed in the intestines if taken orally, all of these drugs must be injected into the skin, either daily or weekly.

FDA approval for these products was based entirely on clinical trial data that demonstrated limited effects in reducing hemoglobin A1c (HbA1c) levels — a measure of how well a patient's blood sugar has been controlled during the previous two to three months.

For example, clinical trial data submitted to the FDA indicated HbA1c was reduced only slightly more in patients using exenatide than in those using a placebo.[1]

Alongside these minimal benefits in controlling blood sugar, incretin-mimetic drugs are associated with a number of serious, potentially fatal risks.

Cardiovascular risks

Clinical studies — both pre- and post-approval — have found that incretin-mimetic drugs may increase risk for adverse cardiovascular diseases events, including heart failure and abnormal heart rhythms, such as atrial fibrillation (a rapid and irregular heart rate). The FDA initially delayed approval for exenatide due to evidence of cardiovascular risks, specifically that the drug might cause heart rhythm abnormalities — evidence that the manufacturer attempted to withhold from the FDA.[2]

Clinical trial data submitted to the FDA also indicate that incretin mimetics as a group are associated with an increase in the incidence of such serious adverse cardiovascular orgevents. For example, atrial fibrillation was twice as common in albiglutide-treated patients (1 percent) as in those taking a placebo (0.5 percent).[3] Likewise, atrioventricular block, another type of abnormal heart rhythm, occurred more than twice as frequently in dulaglutide patients (2.3 percent) as in those taking a placebo (0.9 percent).[4] Despite these worrisome risks, the FDA approved these drugs, but it required manufacturers to conduct postmarketing cardiovascular safety studies.

Pancreatitis and pancreatic cancer

Incretin mimetics also are associated with an increased risk of pancreatitis (inflammation of the pancreas) — which can sometimes lead to death — and pancreatic cancer. While acute pancreatitis may initially have seemingly benign symptoms (such as nausea, vomiting and abdominal pain), it has been found to increase the risk of pancreatic cancer more than tenfold.[5]

A 2011 study in the medical journal Gastroenterology found that there was a tenfold higher rate of reporting cases of pancreatitis and a threefold higher rate of reporting cases of pancreatic cancer to the FDA’s adverse event reporting system for patients using exenatide compared with patients using four other diabetes drugs.[6] This study article was later withdrawn from the Gasteroenterology website, following pressure from the drug’s manufacturer, according to The British Medical Journal.[7]

A 2009 FDA inspection of Amylin Pharmaceuticals (manufacturer of BYETTA) was conducted in response to a complaint from internal company whistleblowers that alleged the "Vice President stated she would be fired if BYETTA received a black box warning for pancreatitis."[8] (A black- box warning is the strongest warning the FDA can require.)

These troublesome reports are consistent with pre-approval clinical studies submitted to the FDA. For example, clinical trial data indicated a fivefold increased rate of pancreatitis in liraglutide-treated patients compared with those taking the diabetes drug glimepiride (AMARYL).[9]

The FDA has issued several drug safety communications describing the risks for acute pancreatitis[10] and required product labeling and patient medication guides for all incretin mimetics to warn about these risks. A black-box warning, however, has not been mandated. Product labels also fail to mention the increased risk for pancreatic cancer.

Thyroid cancer

Incretin mimetics are the only FDA-approved drug products linked to thyroid cancer, and a black-box warning describing this risk is required on product labeling for all incretin mimetics except the BYETTA version of exenatide.[11],[12],[13],[14],[15]

The FDA initially discovered the risk for a type of thyroid tumor, known as a c-cell tumor, during pre-approval animal studies for liraglutide. In fact, the FDA pharmacologists who reviewed the studies recommended against liraglutide’s approval due to concerns about drug- induced thyroid c-cell tumors.[16],[17],[18]

In addition, pre-approval clinical trials reviewed by the FDA found a two- and threefold higher incidence of human thyroid c-cell tumors and papillary thyroid cancer, respectively, in patients treated with liraglutide, in comparison to patients using other diabetes drugs.[19]

In an April 2009 FDA advisory committee meeting, committee members (including several thyroid cancer experts) agreed that liraglutide might cause thyroid cancer.[20] Nevertheless, against the recommendations of four FDA safety experts, the FDA approved liraglutide nine months later.

The link between incretin mimetics and thyroid cancer also has been increasingly recognized in medical and patient safety literature. A 2011 study reported a 4.7-fold higher reporting rate to the FDA of thyroid cancer for exenatide-treated patients in comparison to patients using other diabetes drugs.[21] A 2013 update to this report, published in the medical journal Diabetes Care, found thyroid cancer was reported 18 times more frequently for liraglutide-treated patients in comparison to those using other diabetes drugs.[22]

As these drugs have been more widely used, more cases of medullary thyroid carcinoma — a rare form of malignant human thyroid c-cell tumors — have been reported to the FDA. These reports prompted the FDA to require product labeling revisions that specifically warn against this additional cancer risk.

Other side effects

FDA-approved product labeling for all four of these drugs warn against the risk of worsening kidney function and kidney failure, for which, even without these drugs, diabetic patients are already at increased risk.

Incretin mimetics also are associated with a greater incidence of serious life-threatening hypersensitivity (or allergic) reactions, including sudden swelling of the face, hands, feet or throat.

What You Can Do

Due to limited clinical benefits and a series of serious safety concerns, we recommend that you do not use any incretin-mimetic drug.

You should avoid starting any incretin-mimetic drug if you are not taking it currently. If you are already taking one of these drugs, you should consult your doctor about switching to an equally effective and safer drug for Type 2 diabetes, such as metformin (GLUCOPHAGE), a second- or third-generation sulfonylurea, or insulin.

Along with taking drugs, get regular exercise and eat a healthy diet. These measures are instrumental in controlling blood sugar levels.

References

[1] AstraZeneca Pharmaceuticals. Label: (exenatide (BYETTA). February 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021773s040lbl.pdf. Accessed June 9, 2016.

[2] Parks MH. Food and Drug Administration’s complete response letter to Amylin Pharmaceuticals regarding the new drug application for exenatide (BYDEURON). October 18, 2010. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000OtherActi onLtrs.pdf. Accessed June 9, 2016.

[3] GlaxoSmithKline. Label: albiglutide (TANZEUM). May 2015. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fcad939 -76e7-49cf-af94-4e6aef17901f. Accessed June 9, 2016.

[4] Eli Lilly and Co. Label: dulaglutide (TRULICITY). March 2015. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm? setid=463050bd-2b1c-40f5-b3c3-0a04bb433309. Accessed June 9, 2016.

[5] Munigala S, Kanwal F, Xian H, et al. Increased risk of pancreatic adenocarcinoma after acute pancreatitis. Clin Gastroenterol Hepatol. 2014;12(7):1143- 1150.

[6] Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141(1):150-156.

[7] Hawkes N. Journal withdraws article after complaints from drug manufacturers. BMJ. 2011;342:d2335.

[8] Chuen M. Food and Drug Administration clinical inspection summary to Amylin Pharmaceuticals for BYETTA regarding NDA 21919. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021919s000OtherR.pdf .

[9] Novo Nordisk. Label: liraglutide (VICTOZA) injectable. April 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm? setid=5a9ef4ea-c76a-4d34-a604-27c5b505f5a4. Accessed June 10, 2016.

[10] Food and Drug Administration. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. March 4, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm.

[11] AstraZeneca Pharmaceuticals. Label: exenatide (BYDUREON). March 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022200s019lbl.pdf.

[12] AstraZeneca Pharmaceuticals. Label: exenatide (BYETTA). February 2015. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm? setid=53d03c03-ebf7-418d-88a8-533eabd2ee4f. Accessed June 10, 2016.

[13] GlaxoSmithKline. Label: albiglutide (TANZEUM). May 2015. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm? setid=5fcad939-76e7-49cf-af94-4e6aef17901f. Accessed June 10, 2016.

[14] Eli Lilly and Co. Label: dulaglutide (TRULICITY). March 2015. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=463050bd-2b1c-40f5-b3c3-0a04bb433309. Accessed June 10, 2016.

[15] Novo Nordisk. Label: liraglutide (VICTOZA). April 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5a9ef4ea-c76a-4d34-a604-27c5b505f5a4. Accessed June 10, 2016.

[16] Parola AL. Food and Drug Administration pharmacology review for liraglutide (VICTOZA) NDA 22 -341. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000pharmr_P2.pdf. Accessed June 10, 2016.

[17] Davis-Bruno K. Food and Drug Administration memorandum from pharmacology supervisor for liraglutide NDA 22-341. July 13, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000pharmr_P1.pdf. Accessed June 10, 2016.

[18] Brown PC. Food and Drug Administration. Tertiary pharmacology/toxicology review for liraglutide NDA 22-341. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000pharmr_P1.pdf. Accessed June 10, 2016.

[19] Mahoney KM. Food and Drug Administration clinical safety review for liraglutide injection. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000medr_P2.pdf. Accessed June 10, 2016.

[20] Food and Drug Administration. Summary minutes, April 2, 2009: Endocrinologic and Metabolic Drugs Advisory Committee meeting. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologic andMetabolicDrugsAdvisoryCommittee/UCM192028.pdf. Accessed June 10, 2016.

[21] Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141(1):150-156.

[22] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013;36(7):2118-2125.

[23] Food and Drug Administration. NDA supplement approval letter for liraglutide (VICTOZA) injection. March 2015. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/022341Orig1s023ltr.pdf.