Saxagliptin Okay in Diabetes with Heart Failure, but Take Care

September 25, 2014

VIENNA — Saxagliptin (Onglyza, AstraZeneca/Bristol-Myers Squibb) is safe to use in diabetes patients with heart failure, unless they have very advanced heart failure and concomitant renal insufficiency, experts say.

The link between saxagliptin, a selective dipeptidyl peptidase 4 (DPP-4) inhibitor for the treatment of type 2 diabetes and heart failure, was first reported a year ago, in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-TIMI 53 trial.

The results showed that 3.5% of the type 2 diabetes patients on saxagliptin were hospitalized with heart failure, vs 2.8% of those on placebo (hazard ratio [HR], 1.27; P = .007).

This finding came seemingly out of the blue, and doctors have been struggling with the implications ever since. In February of this year, the US Food and Drug Administration announced that it would review heart-failure risk associated with saxagliptin.

Now a new analysis of this trial, attempting to drill down and identify factors most associated with this increased risk for HF, has been published recently in Circulation and was reported at the European Association for the Study of Diabetes (EASD) 2014 Meeting last week.

It found that the increased risk for heart-failure hospitalization associated with saxagliptin was highest in the first year after patients began taking the drug and that previous heart failure, higher levels of brain natriuretic peptide (BNP), and chronic kidney disease were all associated with increased heart-failure hospitalization.

Skirting the Issue Somewhat…

Reporting this new analysis at EASD, co–primary investigator of SAVOR-TIMI 53, endocrinologist Itamar Raz, MD, of Hadassah Hebrew University Hospital, in Jerusalem, Israel, was asked by one delegate whether saxagliptin is safe to give to elderly patients with many comorbidities.

"The SAVOR-TIMI 53 study contained patients with long disease duration, and they were treated with a large variety of therapies, and many of them had very high HbA1c. If you look at patients who don't have a clear history of HF…the risk that saxagliptin will increase hospitalization for HF is very, very minor, so the answer is yes, this drug is safe," he pronounced.

An analysis by age did not reveal anything untoward, either, he noted: "The risk in old people was the same as it was in young people."

Asked specifically if it were safe to give to patients with prior or existing heart failure, Dr. Raz replied: "These are the patients you should be careful with…those with prior HF," and especially those who also have renal failure and/or high BNP. "Watch them carefully if they are on saxagliptin."

He stopped short, however, of saying he would not use the drug in such patients.

Session chair, Jorgen Rungby, MD, DSsc, of Aarhus University Hospital, Denmark, was also cautious in his response when asked the same question by Medscape Medical News: "I think that [Dr. Raz's] answer is the right one — you have to be careful. You have to be careful with any drug. There is a small signal we will have to consider with the SAVOR-TIMI 53 trial, and it needs further exploration. Would I give it or not? If this were the drug on the desk for this patient, I would give it and observe the patient."

Asked to comment, cardiologist Darren McGuire, MD, MHSc, of the University of Texas Southwestern Medical Center, Dallas — who was also an investigator on SAVOR-TIMI-53 — admitted: "It is challenging to know what to do with this signal."

Drs. Raz and Rungby are "appropriately skirting the issue to some degree, given a) the uncertainty that this is even a real finding — although I believe it is; and b) if real, it has to be woven into the landscape of alternatives," said Dr McGuire.

He added, however, that, given the "number needed to harm" for HF hospitalization from SAVOR — calculated as 133 treated patients for every 1 who would suffer this outcome — he would still use the agent in heart-failure patients with type 2 diabetes, "in the context of the advantages of saxagliptin as a once-daily tablet, almost no risk for hypoglycemia, and absence of weight gain."

"If used for patients with a diagnosis of HF, though, patients should be counseled to pay close attention to HF signs and symptoms that might prompt clinicians, when present, to interrupt therapy well before requiring hospitalization," he noted.

And there is a subgroup of very sick patients in whom Dr. McGuire said he would not use saxagliptin: "For those with advanced HF (NYHA class 3b or 4), especially with concomitant renal insufficiency, I would not use it."

HF Likely a True Effect With Saxagliptin

Heart failure in diabetes patients is increasingly being seen as the "elephant in the room." Most of the large trials of antihyperglycemic agents have not had heart failure as an end point, and heart-failure specialists lament the lack of awareness about HF among diabetologists.

Diabetes drugs other than saxagliptin are known to cause or worsen heart failure, most notably the thiazolidinediones (TDZs), such as pioglitazone.

"Folks are quick to point out that TZDs are a problem with causing or worsening HF, and indeed this opinion is well supported by observations from a number of trials and across the class [differentiating that signal from the present one with saxagliptin]," said Dr McGuire.

However, it should be noted that in SAVOR-TIMI 53, as reported in the new Circulation paper, "the absolute increase risk for HF hospitalization over the 2-year trial period was 0.6% for those without prevalent HF and 1.5% for those with prior HF."

"Annualized, this is 0.3% and 0.75%, rates that are right in the range of incremental HF risk observed with TZDs," he said.

The whole SAVOR investigation team feels similarly that the HF finding is likely real.

"Though unexpected, the incremental risk of heart-failure hospitalization observed with saxagliptin is likely valid, given the large number of events and the prespecification of heart-failure hospitalizations as a component of the secondary end point, together with central blinded adjudication," they write in the Circulation paper.

But Is It a Class Effect? And What Are the Alternatives?

And although only saxagliptin so far among the DPP-4 inhibitors has been linked with heart failure, there was a trend toward a higher risk for HF hospitalization with another agent in this class, alogliptin (Nesina, Takeda Pharmaceuticals), in the EXAMINE study.

And most cardiovascular-outcomes trials with other DPP-4 inhibitors have yet to report.

"I am concerned this HF problem is a class effect," Dr. McGuire said. "Although the EXAMINE analysis of HF with alogliptin was not statistically significant, the point estimate was unfavorable for alogliptin and numerically fairly consistent with the signal with saxagliptin from SAVOR."

And aside from TZDs and DPP-4 inhibitors, it's not really clear what other diabetes therapies are safe, from a heart-failure standpoint — evidence is scant.

Metformin is "probably" safe; sulfonylureas, "we're not sure"; glitazones, "no"; DPP-4 inhibitors, "possibly not, but we need more data"; and for the glucagonlike peptide-1 (GLP-1) receptor agonists, "we just don't know", one heart-failure expert, Barrie (Miles) Fisher, MD, of the Glasgow Royal Infirmary, Scotland, told the EASD meeting in Barcelona last year.

In concluding his talk at EASD in Vienna last week, Dr. Raz said: "Ongoing studies will help to characterize further classwide effects of DPP-4 inhibitors and provide additional safety and efficacy data for treating type 2 diabetes."

One of the most eagerly awaited of these studies is the large cardiovascular-outcomes trial with sitagliptin (Januvia, Merck), the DPP-4 inhibitor that has been on the market for the longest period. Called TECOS, it is due to complete in December 2014.

Dr. Raz reports being on the advisory board for Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, MSD, and Eli Lilly; consulting for Bristol-Myers Squibb/AstraZeneca, Johnson & Johnson, and Eli Lilly; and being on the speaker's bureau for Eli Lilly, Novo Nordisk, AstraZeneca, Roche, and Johnson & Johnson. Dr. McGuire reports honoraria for trial leadership and consultation with GlaxoSmithKline, Takeda Pharmaceuticals, Novo Nordisk, Janssen, Eli Lilly, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Merck, Regeneron, Lexicon, Genentech, and Hoffmann-LaRoche.

European Association for the Study of Diabetes 2014 Meeting; September 18, 2014. Abstract 186

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