DPP-4 Inhibitors and Heart Failure in Diabetes: Be Vigilant

December 10, 2013

MELBOURNE, Australia — Patients with type 2 diabetes who are at high risk for or who already have heart failure should not be precluded from receiving dipeptidyl peptidase-4 (DPP-4) inhibitor glucose-lowering agents, said most experts at the World Diabetes Congress 2013 last week.

Rather, they should be supervised closely for the first 6 months of therapy, because new findings from the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus — TIMI 53 (SAVOR-TIMI 53) trial, reported at the diabetes meeting, indicate that heart-failure cases associated with the use of the DPP-4 inhibitor saxagliptin ( Onglyza, Bristol-Myers Squibb/AstraZeneca) appeared to occur primarily in the first 6 months of use of the drug.

"Thereafter, the difference in hospitalization [for heart failure] was very minor and nonsignificant" between patients receiving saxagliptin and those randomized to placebo in the trial, said Itamar Raz, MD, from Hadassah University Hospital, Jerusalem, Israel, who reported the new analysis at the meeting. Also, there was no evidence that subjects treated with saxagliptin had a more complicated course of heart failure while in the hospital, said Dr. Raz, who is co–primary investigator of SAVOR-TIMI 53.

He told attendees that he believes the finding of a slightly increased risk for heart failure with saxagliptin is likely real and is probably a class effect, because a trend toward an increase in hospitalization for heart failure was also observed in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) study with another DPP-4 inhibitor, alogliptin (Takeda Pharmaceuticals).

But the mechanism is not known — for example, the SAVOR-TIMI 53 investigators found no evidence of a direct effect of saxagliptin on the myocardium, said Dr. Raz. And data from the VIVIDD study with another DPP-4 inhibitor, vildagliptin (Galvus, Novartis), given to patients with HF who were followed for 1 year, didn't demonstrate an increase in HF in the patients who were treated with the drug when reported earlier this year but did show an increase in both systolic and diastolic pressure. "So it might be that it does have some kind of effect on the heart, but we don't really have an explanation," he said.

And unfortunately, there are no echocardiography data from SAVOR-TIMI 53 or EXAMINE to further illuminate the type of heart failure that is occurring, he noted. "It will take time; we are waiting for the TECOS study [cardiovascular outcomes with the DPP-4 inhibitor sitagliptin (Januvia, Merck)] to get an idea whether it's a class effect and/or whether it's by chance," Dr. Raz said.

Further discussion at the meeting centered on whether DPP-4 inhibitors might affect the heart rate, with some data suggesting that there might be glucagonlike peptide (GLP)-1 receptors in the atrium of the heart.

This would undoubtedly have an additional effect, said heart-failure expert Henry Krum, MD, from the Center of Cardiovascular Research and Education in Therapeutics at Monash University, Melbourne, Australia. "Any drug that has been developed for HF or for other indications that increases heart rate has tended to do bad things in these people," he observed. "Any glucose-lowering agent that does this would immediately concern me."

However, at the end of the 2-hour session, which culminated in a panel discussion involving Dr. Raz; Dr. Krum; and co–principal investigator of EXAMINE, Dr. Simon Heller, MD, from the University of Sheffield, United Kingdom; Dr. Krum concluded: "We still don't know what is going on here."

Therapy Choice May Be Lesser of 2 Evils

Debate about this topic has simmered since the results of the SAVOR-TIMI 53 trial and those of the EXAMINE study were reported at the European Society of Cardiology meeting and further discussed at the European Association for the Study of Diabetes conference in September. SAVOR-TIMI 53 and EXAMINE were cardiovascular safety outcomes trials of these relatively new diabetes agents, which unexpectedly showed signals for heart-failure hospitalization.

At that time, some cardiologists in particular said that they would no longer prescribe DPP-4 inhibitors for diabetes patients with preexisting heart failure, at least not until more data were available.

But diabetologists in Melbourne emphasized that treatment decisions still need to be made in patients with type 2 diabetes who have or are at high risk for heart failure when they require another glucose-lowering agent other than metformin.

Jonathan Shaw, MD, MRCP, FRACP, from the Baker IDI Heart and Diabetes Institute, Melbourne, told Medscape Medical News: "There is a lot of uncertainty, but...some of the data we have seen today would probably give me a little bit more of a stronger feeling that this is a real effect on HF. But even if I accepted that [saxagliptin or other DPP-4 inhibitors] definitely precipitate or cause HF, the risk is still relatively small, and I have a feeling that it's still a smaller risk than hypoglycemia."

There is at least as much risk in adding a sulfonylurea or insulin in a person with type 2 diabetes and heart failure, said Dr. Shaw, because these agents are more likely to cause hypoglycemia, and even though this is not necessarily going to cause further cardiac problems, "it's nevertheless a pretty vulnerable population, even if we are just talking about falling over and fracturing the neck of the femur," he stressed. "So I think that for most patients, that risk is probably greater than the possible heart-failure risk."

The advice from cardiologists not to use DPP-4 inhibitors in patients with heart failure until further data are available, is, said Dr. Shaw, "based on thinking that doesn't recognize that you have to make a choice. But the reality is that the other choices may not be good either, and for different reasons, they may actually be worse."

Dr. Heller, also an endocrinologist and one of the lead investigators of EXAMINE, said the history of introduction of new agents in diabetes "is littered with assuming that the medication is going to be great and we should learn the lessons, particularly when safety signals emerge." But he stressed that these types of findings, such as the HF one, are "hypothesis-generating only."

"We didn't expect to see this. I think this causes us to take stock and to discuss it with our patients. I don't think any of the medications we have are perfect, and we need to very thoughtful. [But] if anybody were suggesting a change in clinical therapy as a result of what is a secondary outcome [HF hospitalization], I think they would be doing that prematurely."

Use DPP-4 Inhibitors in HF Patients, but Be Vigilant

Dr. Krum, who summarized the evidence to date with regard to this issue at the meeting, said that "theoretically, DPP-4 inhibitors should result in less heart failure," but the data so far indicate the opposite. He concluded that "we will have to wait for the other large-scale DPP-4 inhibitor studies" to report to glean more information.

But Dr. Heller said that he is concerned that the ongoing cardiovascular-outcome studies with other DPP-4 inhibitors "are not necessarily addressing the issue of HF."

"We have an opportunity now to start designing studies that tackle this hypothesis and test it," he stressed.

In the meantime, the question still remains about what to do with patients at risk for or with HF when they require new hypoglycemic agents.

Dr. Raz said: "If you look at the patients who were in danger of hospitalization for HF with saxagliptin, those were mainly patients known to have HF. In those patients, the hazard ratio for hospitalization for heart failure was about 2.0 [compared with 1.27 in the overall population].

"What I would say is that if you do have a patient with HF and you want to add this drug — and this drug does have a lot of important [beneficial] effects (eg, doesn't cause weight gain, doesn't cause hypoglycemia, etc) — you should follow your patient closely."

Dr. Krum agreed: "From an HF perspective, because I don't lower sugars but I do look after patients with HF, do exactly that. Be very vigilant with the patients at highest risk, who are the ones you identified...previous HF, known [left ventricular] LV dysfunction, and higher risk for HF."

That vigilance should include more frequent visits and regular sequential brain natriuretic peptide (BNP) testing, "which I find very helpful in tracking which direction the patient is heading," Dr. Krum noted, plus clinical assessment such as renal function.

"I think we need to keep a watchful eye. If you need to use [DPP-4 inhibitors], use them, just be very vigilant in the high-risk patients, using the tools that we have," he concluded.

Dr. Raz is co–primary investigator of SAVOR and 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 speakers' bureau for Eli Lilly, Novo Nordisk, AstraZeneca, Roche, and Johnson & Johnson. Dr. Heller is co–primary investigator of EXAMINE. Dr. Krum has previously disclosed receiving travel reimbursements from Pfizer. Dr. Shaw reports receiving research funding from all major pharmaceutical companies that market diabetes medications.

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