Heart-Failure Data for Alogliptin Prompt More Debate at ACC

March 31, 2014

WASHINGTON DC — The possible risk of heart failure associated with the use of the dipeptidyl peptidase-4 (DPP-4) inhibitor drugs for type 2 diabetes is once again in the spotlight, with new data reported at the American College of Cardiology 2014 Scientific Sessions apparently showing little risk of this with alogliptin (Nesina, Takeda Pharmaceuticals).

Presenting the new subanalyses on heart failure from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) study in a poster presentation, authors Faiez Zannad, MD, from Centre Hospitalier de Lorraine, Nancy, France, a heart-failure expert, and William White, MD, from University of Connecticut School of Medicine, Farmington, both told Medscape Medical News they were reassured by the data.

"We have [looked at HF]…and the result is that after a number of analyses and subanalyses, in the whole population and in subgroups, the message is that alogliptin is very safe and does not increase the risk of new-onset heart failure," Dr. Zannad told Medscape Medical News.

It also "does not increase the risk of readmission in patients with a history of heart failure, and therefore if you have got a high-risk patient with type 2 diabetes, it's certainly safe to use this drug," he said.

Dr. White agreed: "I think this is a major advance in the knowledge base, because now we have really systematically and carefully analyzed mortality, causes of mortality, and heart failure, according to different kinds of background risk, and have really not found a problem with this drug vs placebo."

But other doctors not involved with the EXAMINE trial were more circumspect and said they would be withholding judgment until the heart-failure analyses from EXAMINE were properly published and they could better scrutinize the data.

Caution Required Until Full Data Are Dissected

Heart-failure specialist Henry Krum, MD, from Monash University, Melbourne, Australia, told Medscape Medical News: "My view is a little bit more cautious. I think until this is sorted out I would be a little concerned about giving DPP-4 inhibitors to patients with established heart failure because I think there is still a signal there, an increased risk of heart-failure hospitalization, particularly in the highest-risk subgroups."

Dr. Krum indicated that he was referring to the "signal" overall for a potential increased risk of heart failure with this drug class. Concerns first arose with the release of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) trial last summer, with the DPP-4 inhibitor saxagliptin (Onglyza/Kombiglyze XR, Bristol-Myers Squibb/AstraZeneca), which unexpectedly showed a signal for an increase in heart-failure hospitalizations in diabetes patients randomized to the drug.

"The signal in EXAMINE is pretty weak, I would have to agree with that," Dr. Krum noted. "And if SAVOR didn't exist, we probably wouldn't even be having this discussion. It's just that this has to be looked at in the context of SAVOR."

John McMurray, MD, another heart-failure expert, from the University of Glasgow, Scotland, agrees: "The most robust data we have to date come from SAVOR-TIMI 53," he told Medscape Medical News.

Naveed Sattar, MD, also from the University of Glasgow, has similar concerns: "I think you have to take these new results at face value. They do seem to provide some reassurance, but whether there is sufficient power to really exclude an effect of alogliptin on risk for heart failure, or hospitalization for heart failure, is uncertain without being able to see the actual data. Hopefully full disclosure in a published paper will help resolve these issues."

If these new EXAMINE heart-failure data do turn out to be robust, Dr. McMurray said, "that would suggest that one of the trial results is a fluke — a chance finding, that there was some important difference between the trial populations, or that there is a difference between drugs in the class," he said. "There will continue to be some concern until we get more trial results."

Dr. Sattar agrees: "I believe the results of TECOS — which is [studying] sitagliptin (Januvia, Merck) over a much longer period, will be important to provide further guidance in this area." The TECOS study is due to complete in December 2014.

"For now I believe some caution may be appropriate," Dr. Sattar said.

New Data Reported in Posters at ACC

Both saxagliptin and alogliptin emerged in the new US Food and Drug Administration (FDA) era that requires makers of all type 2 diabetes agents to conduct a cardiovascular-end-point study to show the drugs are safe. Both SAVOR-TIMI 53 and EXAMINE were reported at European Society of Cardiology meeting last year and published simultaneously in the New England Journal of Medicine.

In SAVOR-TIMI 53, 16,492 patients with type 2 diabetes at high risk for cardiovascular events or who had a history of cardiovascular events were randomized to saxagliptin 5 mg/day or placebo for approximately 2 years. There was no difference between the 2 groups in the primary end point — a composite of cardiovascular death, myocardial infarction, or ischemic stroke.

But seemingly out of the blue, saxagliptin was associated with a significant 27% increased risk for hospitalizations for heart failure, a component of the prespecified secondary end point. Further analysis of SAVOR reported at the World Diabetes Congress in Melbourne in December indicated that heart-failure cases associated with the use of saxagliptin appeared to occur primarily in the first 6 months of use of the drug.

And in February, the FDA said it was reviewing the possible risk of heart failure among patients with type 2 diabetes treated with saxagliptin.

EXAMINE was the cardiovascular-outcomes study for alogliptin, which randomized fewer patients — 5380 with type 2 diabetes — but they were sicker than the SAVOR population because they had had an acute coronary syndrome (ACS) within the previous 15 to 90 days.

The primary analysis also showed no increased cardiovascular risk with alogliptin. But no heart-failure data were initially available from EXAMINE.

Now, at the ACC meeting, in 2 poster presentations, the researchers have reported 2 subanalyses. The first showed no effect on cardiovascular mortality in those taking alogliptin (hazard ratio [HR], 0.85 compared with placebo), or in sudden cardiac death (2.2% with alogliptin compared with 2.7% with placebo; HR, 0.80).

The second poster detailed heart-failure outcomes and cardiovascular safety in heart-failure patients in the study.

In those with type 2 diabetes and recent ACS, the prespecified composite cardiovascular outcome of first occurrence of all-cause mortality, nonfatal MI and stroke, urgent revascularization due to unstable angina, and hospitalization for heart failure was similar for alogliptin compared with placebo [HR, 0.98; 95% CI, 0.86–1.12].

Within this composite end point, hospitalized heart failure occurred in 3.1% of patients on alogliptin vs 2.9% on placebo [HR, 1.07; 95% CI, 0.79–1.46].

In addition, alogliptin neither induced new-onset heart failure nor worsened heart-failure outcomes in patients with a history of heart failure and/or with markers for heart failure (elevated BNP levels).

What to Do Now About Prescribing DPP-4 Inhibitors

Dr. White said he would say now, unequivocally, to diabetologists that they should not worry about heart failure with alogliptin.

"I think that we have done our due diligence: we see a 20% reduction in mortality, we see no increase in heart failure even in the sickest group or according to BNP, and actually the BNP levels seem to drift down while patients are on the drug, not up. And other little things like more people should get edema, more people should need diuretics, but we haven't seen any of that."

He added that the full heart-failure data will be published at a future date.

Despite these reassurances, Dr. Krum said there are a number of things he'd like to see from EXAMINE. "I'd like to see the accrual of the heart-failure hospitalization as a Kaplan-Meier plot, a bit like what SAVOR did, the time course of things."

And because EXAMINE was a post-ACS population, "there would be some patients who had heart failure before the ACS, some who had heart failure because of the ACS, and there would be some patients who had heart failure years ago and actually don't currently have symptoms.

"So I think there needs to be further exploration within those groups. If there is a signal, and I agree the signal is very weak and may just be the play of chance, is it within any of those groups? We don't know — I haven't seen that data. They have to publish it."

In the meantime, he said that while he doesn't generally, as a heart-failure specialist, prescribe these drugs, he wouldn't be overly concerned if someone who doesn't have heart failure received a DPP-4 inhibitor.

"I would still say be vigilant in terms of monitoring the patient, asking them about [heart-failure] symptoms, check them out clinically, but I wouldn't do any more than that, I don't think they need to have BNPs or echos or anything like that.

"If somebody came to me with these drugs on board, already prescribed, I wouldn't stop them. I'd be very comfortable if patients are well-established on them, haven't had any decompensations, to continue therapy but with increased vigilance."

And in someone with established heart failure, "if they came to me on a DPP-4 inhibitor, I would be supervigilant, particularly if it's a new initiation, for the first few months of therapy.

"The patient I'm thinking I wouldn't start on a DPP-4 inhibitor is someone who has current, established heart failure. If they had something 10 years ago and they are perfectly well now, I would be fine with that," he concluded.

Drs. Zannad and White are EXAMINE investigators. Dr. Sattar has consulted for AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi, and Boehringer Ingelheim. Dr. Krum has served on an advisory board for DPP-4 inhibitors for Astra Zeneca. Glasgow University, Dr. McMurray's employer, is paid for his time spent as a steering-committee member, data-safety-monitoring-board member, and end-point-committee member in diabetes trials by Bayer, GlaxoSmithKline, Lilly, Merck, Novartis, Sanofi, and Oxford University.

American College of Cardiology 2014 Scientific Sessions. Abstract 1152-248, Abstract 1152-249, presented March 29, 2014.

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