FDA panel recommends new safety labeling for Onglyza


An FDA advisory panel recommended label changes for the diabetes drug Onglyza after results from a cardiovascular outcomes trial revealed an increased risk for heart failure.

The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 14-1 Tuesday in favor of including new safety information for Onglyza (saxagliptin, AstraZeneca). The recommendation follows EMDAC review of the results of the SAVOR trial, which found a 27% increase in the rate of hospitalization for heart failure, as well as an increase in all-cause mortality, in patients who had taken the drug.

The majority of the panel opted not to vote in favor of more serious actions, including label changes with restricted distribution of the drug or withdrawing saxagliptin from the market. The panel also voted 13-1 (with one abstention) that the SAVOR trial demonstrated that saxagliptin has an acceptable CV risk profile.

Researchers for the SAVOR trial analyzed data from 16,492 patients with type 2 diabetes for 2 years who had an established risk or high risk for CVD. During the course of the prospective, randomized, double blind, placebo-controlled trial, 493 patients assigned saxagliptin (6%) were hospitalized or died of heart failure vs. 432 patients (5.3%) assigned a placebo (HR = 1.14; 95% CI, 1-1.3).

“There is a public health implication of this finding — a substantial number of subjects with hospitalization for heart failure events, regardless of treatment assignment, had recurrent events and/or died during the trial,” the researchers wrote. “A safety signal for heart failure was not previously observed in the saxagliptin clinical program.”

Approved by the FDA in 2009, saxagliptin is part of a class of diabetes drugs known as DPP-IV inhibitors used to control glucose levels in patients. Since 2008, the FDA has required agents in that class to undergo additional studies to examine their safety after concerns of a link between the drugs and an increased risk for heart failure.

Speaking on behalf of AstraZeneca, Jay S. Skyler, MD, MACP, of the University of Miami Miller School of Medicine, said the trial findings can be managed in the context of an updated label with new patient safety information. Saxagliptin, he said, remains an effective glucose-lowering agent with a low risk for hyperglycemia and no weight gain.

“There are always going to be side effects,” Skyler told the committee. “We always need to weigh risk vs. benefit.”

Some panelists said the findings were difficult to interpret and called for more long-term studies, noting that the SAVOR trial included only participants who were already at a high risk for heart disease and may not apply to all patients with type 2 diabetes.

Speaking during the public comment portion of the meeting, Robert Ratner, MD, FACP, FACE, chief science and medical officer for the American Diabetes Association, questioned the SAVOR trial results, calling the outcome the result of “data drenching” that does not take typical patients into account.

“We have to ask ourselves what is clinically significant as opposed to statistically significant,” Ratner said. “No definitive conclusions can be drawn from these observations.”

Some consumer advocates, however, found the heart failure risk to be too great. Bonnie Arkus, RN, consumer member of the EMDAC, voted the drug be withdrawn.

“As a consumer, I feel the risk–benefit is just not there,” said Arkus, who also voted that the drug does not have an acceptable CV risk profile. “The heart failure question … what is causing this is baffling. It’s just too much of a risk to take this drug as a consumer.”

Addressing the panel, consumer health advocate Sidney Wolfe, MD, also said label changes are not enough. He asked that the drug be recalled.

“This drug has no unique benefits whatsoever,” said Wolf, founder of Public Citizen’s Health Research Group. “And, what appear now to be some unique risks.”

The panel’s recommendations are nonbinding, although the FDA often follows its suggestions.

Robert J. Smith, MD, chair of the EMDAC and a professor of endocrinology at Brown University’s Alpert Medical School, said label changes that reflect the actual data may be difficult.

“There are challenges in how to handle the labeling in connecting it to the actual data,” Smith said after the vote. “The three issues most significant for me are the heart failure risk, and … what I would call unresolved risks regarding pancreatitis and renal effects.

“One of the things that make the labeling challenging is we do know that risk goes up with certain groups of patients, but the risk is not limited to those subgroups,” Smith said. “This doesn’t lend itself to simply nonuse in certain patients … so that requires some careful thought in how the labeling is done.” – by Regina Schaffer

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SAVOR-TIMI 53 raises bar for CV outcome trials in diabetes.


When added to standard care in patients with type 2 diabetes at high CV risk, saxagliptin neither reduced nor increased risk for ischemic events, according to results from the SAVOR-TIMI 53 trial.

Saxagliptin (Onglyza, AstraZeneca and Bristol-Myers Squibb) was also shown to improve glycemic control, but was associated with a small increase in the rate of hospitalization for HF.

The multicenter, randomized, double blind, placebo-controlled, phase 4 trial was designed to determine whether saxagliptin was noninferior to placebo when added to background therapy, for the composite endpoint of CV death, nonfatal MI or nonfatal ischemic stroke, Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School and Chief Medical Editor of Cardiology Today’s Intervention, said at an ESC Congress 2013 press conference.

During a mean follow-up of 2.1 years, the primary endpointoccurred in 7.3% of patients assigned saxagliptin compared with 7.2% assigned placebo (HR=1.00; 95% CI, 0.89-1.12;P=.99 for superiority; P<.001 for noninferiority). An on-treatment analysis yielded similar results (HR=1.03; 95% CI, 0.91-1.17).

The major secondary endpoint, a composite of CV death, MI, stroke and hospitalization for unstable angina, coronary revascularization or HF, occurred in 12.8% of patients assigned saxagliptin compared with 12.4% assigned placebo (HR=1.02; 95% CI, 0.94-1.11). Of note, the saxagliptin group had more hospitalizations for HF (3.5% vs. 2.8%; HR=1.27; 95% CI, 1.07-1.51). In addition, a prespecified secondary endpoint of all-cause mortality occurred in 4.9% of patients assigned saxagliptin compared with 4.2% assigned placebo (HR=1.11; 95% CI, 0.96-1.27).

“The high risk of hospitalization for HF was unexpected, but it was a predefined adjudicated endpoint. Therefore, it does merit further evaluation given the history of other diabetic agents and HF,” Bhatt said. “Additional analyses are ongoing and preliminary data suggest that the risk is highest in those with elevated baseline clinical risk for HF, such as a history of prior HF and/or elevated BNP levels at baseline.”

Fewer patients assigned saxagliptin required the addition or increase of any new antidiabetic medications (23.7% vs. 29.3%; HR=0.77; 95% CI, 0.73-0.82) or the initiation of insulin therapy for more than 3 months (5.5% vs. 7.8%; HR=0.7; 95% CI, 0.62-0.79). Reductions in blood glucose were also greater with saxagliptin, with mean reductions in HbA1c of 0.5% at 2 years in the saxagliptin group compared with 0.2% in the placebo group (P<.001). More patients assigned saxagliptin achieved or maintained goal HbA1c <7% (40% vs. 30.3%; P<.001). About 15% of patients in the saxagliptin group reported at least one hypoglycemic event compared with 13.4% of patients in the placebo group (P<.001). Hospitalization for hypoglycemia was infrequent and similar between groups (0.6% vs. 0.5%; P=.33).

Additionally, saxagliptin was associated with reduced development and progession of microalbuminuria.

“It is very encouraging that within such a short time, 2 years of follow-up, that saxagliptin has demonstrated a beneficial effect on the kidney,” researcherItamar Raz, MD, head of the diabetes unit, department of medicine, Haddassah University Medical Center, Jerusalem, told Cardiology Today.

Rates of pancreatitis were similar with saxagliptin and placebo (0.3% for both; P=.77). Five cases of pancreatic cancer were reported in the saxagliptin group compared with 12 in the placebo group. The incidence of other prespecified safety endpoints were balanced, Bhatt said.

Premature discontinuation of the study drug occurred more in the placebo group (20.8% vs. 18.4%; P<.001).

“There is still a great need to bring patients to HbA1c target and we know today that we only have 50% to 60% of diabetes patients at target. [Saxagliptin] is a safe drug that was not shown to do CV harm, as was shown in the primary and secondary endpoint results,” Raz said.

In The New England Journal of Medicine study, the researchers acknowledged “there remains a strong clinical need to identify antihyperglycemic agents that are, at a minimum, safe and that can potentially reduce cardiovascular complications.”

Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. – by Katie Kalvaitis

Source: Endocrine Today.