CHICAGO — New data from 2 studies further inform upon the risk of heart failure with dipeptidyl peptidase-4 (DPP-4) inhibitors, used to treat type 2 diabetes, but the results are conflicting and therefore do not provide any quick answers.

Both trials were reported in the same oral session at ICE/ENDO 2014 last week, and they provide some of the first information with regard to the heart-failure outcomes with sitagliptin (Januvia, Merck), the DPP-4 inhibitor that has been on the market for longest.

In one, a retrospective cohort study using the Cleveland Clinic electronic health record (EHR) system, patients with type 2 diabetes who received a prescription for metformin and a DPP-4 inhibitor had a significant, albeit small, increased risk for congestive heart failure compared with those who received metformin and other oral antidiabetic agents. These findings were reported by Subramanian Kannan, MD, currently of Narayana Health City, Bangalore, India.

In the other trial — a very large cohort of "real-world" type 2 diabetes patients — starting DPP-4–inhibitor therapy was not associated with an increased risk for cardiovascular disease, including heart failure, compared with those initiating non–DPP-4 inhibitors. Indeed, heart failure was seen less frequently in those taking DPP-4 inhibitors, said Allison B. Goldfine, MD, of Joslin Diabetes Center, Boston, Massachusetts, who presented the findings.

One of the chairs of the session, John Muir Connell, MD, from the University of Dundee, Scotland, said Dr. Goldfine's trial, which has not yet been published, "would be an important one to have out there, because it's a very large cohort. The data look extremely reassuring, and I think prescribers need to have access to that information.

"The power of these studies is that essentially they are community based and they are real-life studies — the concern that everyone has, I guess, about the big pharma-sponsored…trials is that they are not 'real life.' They select out so many patients that you really don't know what they are telling you about how to initiate drugs in the community," Dr. Connell told Medscape Medical News.

Some of First Data on HF with Sitagliptin; "Small" Effect on HF

The contentious issue of whether there is an increased risk for heart failure associated with DPP-4 inhibitors, or "gliptins," arose following unexpected findings with saxagliptin (Onglyza or Kombiglyze XR, Bristol-Myers Squibb/AstraZeneca) from the SAVOR-TIMI 53 trial in patients with type 2 diabetes at high risk for, or with a history of, cardiovascular events.

In the trial, reported in September 2013, a significant 27% increased risk for hospitalizations for heart failure came seemingly out of the blue, and the US Food and Drug Administration (FDA) is currently reviewing this risk. A similar signal, albeit not significant and in a sicker patient population, emerged from the EXAMINE trial with alogliptin (Nesina, Takeda Pharmaceuticals).

Physicians have been concerned about this potential side effect of DPP-4 inhibitors ever since and are particularly keen to establish whether, if this is a real effect, it applies to all agents in this class.

At ICE/ENDO 2014, Dr. Kannan reported on 13,185 patients 18 years of age or older with type 2 diabetes seen in the outpatient clinic and not on insulin or undergoing dialysis at baseline. They received a prescription for metformin in combination with either a sulfonylurea (n = 9419), a thiazolidinedione (TZD) (n = 1846), a DPP-4 inhibitor (n = 1487), or a glucagonlike peptide-1 (GLP-1) receptor agonist (n = 433).

The patients were followed for mortality, coronary artery disease, and congestive heart failure by documentation in EHR and Social Security Death Index. Cox multiple regression models were used to compare cohorts. Combination therapy with metformin plus sulfonylureas served as the comparator group.

The median follow-up was 4 years. There were a total of 1077 deaths, 1733 coronary artery disease (CAD) events, and 528 congestive heart failure events in 55,110.76 person-years of follow-up. No statistically significant difference in the risk for overall mortality or CAD was observed among the different drug combinations.

But there was a higher risk for congestive heart failure observed with metformin plus DPP-4–inhibitor use (hazard ratio, 1.104; 95% CI, 1.04–1.17; P = 0.001).

"Consistent with recent results, our results raise concern for an increased risk of CHF with use of DPP-4 inhibitors," Dr. Kannan concluded.

But in a question-and-answer session, audience member S. Mitchell Harman, MD, PhD, of the Phoenix VA Health Care System, Arizona, commented that these were "relatively small effects; one would like to see these data analyzed in terms of number needed to treat or numbers of excess cases per year, for each of these treatments.

"For those of us who actually have to prescribe these meds, it's useful to have a sense of how many patients we might actually be causing problems [for] when we write one of these prescriptions," Dr. Harman added.

Dr. Kannan replied that this was an important point, "and we will look at this when we prepare the manuscript."

Another audience member asked if Dr. Kannan thought this was a "class effect" of DPP-4 inhibitors; he replied that no subgroup analysis had been performed to enable this question to be addressed. But he did note that because of when the study was conducted, the vast majority of patients were taking sitagliptin, the first DPP-4 inhibitor to be approved in the United States.

Presenting her findings, Dr. Goldfine said it was a similar picture for their study, conducted using commercial insurance claims data from 2005 to 2012. Although saxagliptin, linagliptin (Jentadueto, Trajenta, Boehringer Ingelheim/Lilly), and alogliptin were included, the vast majority of participants were taking sitagliptin, she noted.

No Increase in HF With Gliptins in Those With or Without CVD at Baseline

Dr. Goldfine said the objective of the study was to evaluate the risk for cardiovascular disease, including myocardial infarction (MI), stroke, coronary revascularization, and heart failure associated with DPP-4–inhibitor use in type 2 diabetes in patients with or without baseline cardiovascular disease.

Among patients aged 40 years and older with type 2 diabetes, 2 mutually exclusive exposure groups were selected: DPP-4–inhibitor combination therapy (DPP-4 inhibitor plus metformin) and non–DPP-4–inhibitor combination therapy (metformin plus other non–DPP-4–inhibitor drugs).

The primary end point was a composite cardiovascular disease outcome including MI, stroke, coronary revascularization, and heart failure, defined with a hospital-discharge diagnosis or procedure code. The secondary end points were the individual components of the primary endpoint.

To control for baseline confounders, a propensity-score matching method was used to compare the risk for CVD in DPP-4–inhibitor initiators compared with non–DPP-4–inhibitor initiators, with and without baseline CVD.

The propensity-score–matched hazard ratio for composite CVD was 0.90 for DPP-4–inhibitor vs non–DPP-4–inhibitor therapy in patients with baseline CVD.

Among patients with no baseline CVD, this figure was 0.95 for the same comparison.

The propensity-score–matched hazard ratio for hospitalization for heart failure was also not increased with DPP-4 inhibitors.

There was also a lower risk of getting a new prescription for loop diuretics among those taking DPP-4 inhibitors compared with those who weren't (HR, 0.74), she noted.

There "were many limitations to our type of work, [but] initiation of DPP-4–inhibitor therapy as used in the community did not appear to be associated with a higher risk of composite cardiovascular disease, including heart failure, compared with the initiation of non–DPP-4–inhibitor glycemic agents," Dr. Goldfine commented.

Nor was there any increased risk in any of these outcomes in those with cardiovascular disease at baseline, she added.

TECOS Findings Will Be Key; Expected Next Year?

Session chair Dr. Connell said, "You have a very large cohort and 4 different DPP-4 inhibitors; presumably you could do a post hoc analysis to see if there was a specific drug effect vs a class effect?"

Dr. Goldfine said they could but had not done so yet, and she reiterated that the vast majority of participants in her study were "on sitagliptin, as that was marketed first, and then we had lesser numbers of the others."

All eyes are therefore on the ongoing TECOS study, a cardiovascular-outcomes trial with sitagliptin, which is due to complete in December 2014 and will yield more information on heart failure with this agent.

Dr. Kannan reported no relevant financial relationships. Dr. Goldfine reports receiving support in the form of materials and supplies from Amneal Pharmaceuticals; Lifescan, a division of Johnson & Johnson; Novo Nordisk; Nestle Health Science; and Mercodia. Dr. Connell reported no relevant financial relationships.

Joint Meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014; June 23, 2014. Abstract OR34-3, Abstract OR34-6


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