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Another drug for Type 2 diabetes has been approved by the Food and Drug Administration (FDA) despite clear warning signs that it causes damage to the liver. Notwithstanding the availability of many other drugs for Type 2 diabetes, some with equal or better efficacy and fewer risks, on Jan. 25, 2013, the FDA approved Takeda Pharmaceuticals USA Inc.’s application for alogliptin (NESINA) on the manufacturer’s third try.[1]
That approval decision applied to three drugs: alogliptin alone,...
Another drug for Type 2 diabetes has been approved by the Food and Drug Administration (FDA) despite clear warning signs that it causes damage to the liver. Notwithstanding the availability of many other drugs for Type 2 diabetes, some with equal or better efficacy and fewer risks, on Jan. 25, 2013, the FDA approved Takeda Pharmaceuticals USA Inc.’s application for alogliptin (NESINA) on the manufacturer’s third try.[1]
That approval decision applied to three drugs: alogliptin alone, the combination of alogliptin and metformin (KAZANO)[2], and the combination of alogliptin and pioglitazone (OSENI)[3], all of which were approved simultaneously. (See table for warnings related to the two combinations.)
The FDA found Takeda’s initial application unacceptable because of evidence of cardiovascular risks.[4] It requested a new clinical trial to further assess the cardiac risks of alogliptin. In April 2012, Takeda submitted data from the requested heart study trial. Unfortunately for the manufacturer, the new cardiac risk trial revealed evidence of another disturbing adverse event: liver toxicity. The FDA, again, decided not to approve the application for alogliptin.
However, in July 2012, Takeda submitted a third application with data from eight additional clinical trials which, when combined with data from the earlier studies, showed less liver toxicity. The FDA accepted Takeda’s assessment that the drug did not pose a significant risk of liver damage, and it approved alogliptin.
Limited evidence of benefit
Alogliptin belongs to a class of drugs called gliptins. They inhibit an enzyme that breaks down a hormone called glucagon-like peptide-1(GLP-1), thus prolonging the hormone’s effects. GLP-1, in turn, stimulates the pancreas to secrete insulin.
Like many other drugs recently approved for treating Type 2 diabetes, alogliptin was approved based solely on its effects on a so-called surrogate marker — in this case, levels of hemoglobin A1c or glycosylated hemoglobin in the blood — rather than any evidence of improvement in clinically meaningful outcomes, such as more patients surviving or fewer patients experiencing cardiovascular disease or other diabetic complications.
Glycosylated hemoglobin is a measure of how well a diabetic patient’s sugar has been controlled during the preceding two to three months. In general, physicians try to maintain diabetic patients’ hemoglobin A1c levels at 7 to 7.5 percent. Levels greater than 10 percent indicate very poorly controlled blood glucose.
There are three available doses of alogliptin: 6.25, 12.5 and 25 milligrams (mg).[5] Results from clinical trials testing alogliptin showed that the 25 mg dose alone only modestly reduced hemoglobin A1c levels.[6]
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Safety Warnings for Alogliptin and Its Combinations
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Liver toxicity with alogliptin[10]
The most worrisome adverse reaction seen with alogliptin is liver toxicity. This serious adverse effect first came to the FDA’s attention when the agency received five reports of liver damage experienced by patients treated with alogliptin in Japan after the drug had been approved by regulators there. Takeda submitted these reports to the FDA in 2012 along with data from the clinical trial assessing the drug’s cardiac risks.[11] Among the five cases of liver damage mentioned in the reports, there was one death.
The case reports were carefully reviewed for the FDA by an internationally recognized expert in liver toxicity, Dr. Leonard Seeff.[12] Seeff concluded that two of the cases were “probably” related and two were “probably to highly likely” related to alogliptin use.
One case of liver failure involved a 66-year-old man who had been taking pioglitazone and another gliptin but was switched to alogliptin.[13] After he used alogliptin for one month, a routine blood test for liver enzymes, which is used to detect liver injury, showed an over 35-fold increase above normal levels. Although the patient reported no symptoms, he was hospitalized, and alogliptin was discontinued. No other causes could be found for liver damage, and the patient recovered.
In addition to the five postmarketing reports from Japan, data from the study assessing cardiovascular risks Takeda submitted to the FDA in April 2012 — in its second attempt to get alogliptin approved — also showed that alogliptin-treated patients (compared with control group patients) were more likely to have increased blood levels of liver enzymes.[14] Takeda found similar results in the other randomized trials presented in its second application for approval of the drug.
Some at the FDA were clearly worried about liver toxicity when the agency was considering whether to approve Takeda’s second application for alogliptin: One senior FDA official stated, “The incidence in marked [liver enzyme level] elevations ... was only noted in alogliptin-treated patients [in the cardiac risk study].” Even when pooling the data from 12 clinical trials submitted in 2011, there were still more cases of extremely high enzyme levels in alogliptin-treated patients than there were in patients in control groups not receiving alogliptin. The senior FDA official added that the increase in signs of serious liver toxicity among alogliptin-treated patients “was sufficient to give FDA pause in approving alogliptin at that time.”[15]
However, in its third and final application for approval submitted to the FDA, Takeda provided data from eight additional clinical studies as well as more data from the cardiac risk study. When Takeda combined all patients with any, even mild, elevations of liver enzyme levels, there were only very slight differences between treated and control groups. This enabled the FDA to conclude that the risk of serious liver damage was low enough to grant approval. Nevertheless, the data show that there were consistently more alogliptin-treated patients than control patients with very high elevations.
Label fails to reflect risks
The FDA is still clearly aware of the concerns about liver toxicity (among other adverse events) and required, in its approval letter to Takeda, that the company monitor postmarketing reports for the next five to 10 years, not only for liver toxicity but also for pancreatitis, severe allergic reactions and kidney damage.
Unfortunately, both patients and health care providers are left partially in the dark, without easy access to important information regarding the risks of liver toxicity associated with alogliptin that could help them make better-informed decisions about whether to use it. One would never know from reading alogliptin’s label the severity of the threat of liver toxicity caused by the drug.[16] The label states, “There have been post-marketing reports of fatal and non-fatal hepatic [liver] failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause.” The label omits all references to those patients with the most severely increased enzyme levels, which were the most important cases, and fails to disclose that for some cases of liver damage, there was a high probability that alogliptin was the cause.
What You Can Do
There are a number of effective and safer alternatives for the treatment of Type 2 diabetes (see “Type 2 Diabetes: A Guide to Prevention and Treatment” in the May 2014 issue of Worst Pills, Best Pills News). We list alogliptin as a Do Not Use drug because of the potential for serious liver damage. If you are taking alogliptin, talk to your doctor about changing to another, safer drug for treating diabetes. You should not stop taking any prescription drug without first talking to the prescribing health care provider.
References
[1] Food and Drug Administration. NDA Approval — alogliptin. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/022271Orig1s000ltr.pdf.
[2] Food and Drug Administration. NDA Approval — alogliptin and metformin. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/203414Orig1s000ltr.pdf.
[3] Food and Drug Administration. NDA Approval — alogliptin and pioglitazone. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/022426Orig1s000Ltr_1_.pdf.
[4] Food and Drug Administration. Other Action Letters: Alogliptin. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000OtherActionLtr.pdf.
[5] Food and Drug Administration. Nesina (alogliptin) drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022271s000lbl.pdf. Accessed June 5, 2014.
[6] Ibid.
[7] Ibid.
[8] Food and Drug Administration. Kazano (alogliptin and metformin HCl) drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203414s000lbl.pdf. Accessed June 5, 2014.
[9] Food and Drug Administration. Oseni (alogliptin and pioglitazone) drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022426s000lbl.pdf. Accessed June 5, 2014.
[10] Food and Drug Administration. Other Reviews — alogliptin. October 9, 2008. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022426Orig1s000OtherR.pdf.
[11] Center for Drug Evaluation and Research. Summary Review — alogliptin. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000SumR.pdf.
[12] Center for Drug Evaluation and Research. Summary Review — alogliptin. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000SumR.pdf.
[13] Center for Drug Evaluation and Research. Summary Review — alogliptin. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000SumR.pdf.
[14] Center for Drug Evaluation and Research. Statistical review — alogliptin. May 27, 2008. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000StatRedt.pdf.
[15] Center for Drug Evaluation and Research. Summary Review — alogliptin. Jan. 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022271Orig1s000SumR.pdf.
[16] Food and Drug Administration. Nesina (alogliptin) drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022271s000lbl.pdf. Accessed June 5, 2014.
