New CARMELINA Analysis: No Heart Failure Risk With Linagliptin

Patients with type 2 diabetes who are at high cardiovascular risk do not have an increased likelihood of heart failure-related outcomes if they are given the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta, Lilly/Boehringer Ingelheim) in addition to standard of care, confirms a pre-planned secondary analysis of data from the cardiovascular outcomes trial CARMELINA.

CARMELINA included almost 7000 patients with type 2 diabetes and concomitant atherosclerotic cardiovascular disease and/or kidney disease randomized to once-daily oral linagliptin 5 mg or placebo, alongside standard care.

The main results were presented at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting in October and published online on November 9 in JAMA. As reported by Medscape Medical News at the time, the data were reassuring and showed that linagliptin was safe, in that there was no adverse impact on cardiovascular or renal events in the study population.

But a preplanned analysis of heart failure endpoints was warranted as the SAVOR-TIMI 53 trial in 2013 had revealed that another DPP-4 inhibitor, saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) increased the risk for heart failure hospitalization over placebo when added to usual care in type 2 diabetes. This entirely unexpected finding raised concerns over the use of DPP-4 inhibitors in patients with type 2 diabetes at high risk of heart failure events.

The current analysis, which was published online in Circulation on November 11 and simultaneously presented at the American Heart Association (AHA) Scientific Sessions 2018, looked at rates of heart failure hospitalization, alongside other heart failure and cardiovascular outcomes.

It showed no significant difference between linagliptin and placebo in terms of heart failure hospitalizations, alone or in combination with cardiovascular death, or rates of recurrent heart failure hospitalization.

Lead author Darren K. McGuire, MD, a cardiologist from UT SouthWestern Medical Center, Dallas, Texas, and colleagues write that the findings "demonstrate that linagliptin did not affect the risk for heart failure hospitalization or related heart failure outcomes, overall or across selected subgroups of interest."

They add, "These data provide further support that linagliptin may be safely used, without concerns for increasing heart failure risk, in a high-risk population of individuals with [type 2 diabetes] with concomitant atherosclerotic cardiovascular disease and/or kidney disease."

Comprehensive Analysis of Heart Failure Outcomes in CARMELINA

In an accompanying editorial, Faiez Zannad, MD, PhD, and Patrick Rossignol, MD, PhD, Institut lorrain du Cœur et des Vaisseaux Louis Mathieu, France, say that the investigators "should be complemented" on their use of numerous heart failure-related endpoints.

"To our knowledge, this is the first time that such a comprehensive analysis of heart failure outcomes is provided in a clinical trial."

They caution, however, that there is more work to be done on understanding how different endpoints compete, particularly in relation to the risk of death, and "whether they may be influenced equally by a given therapeutic intervention."

Referring to the ongoing debate over the heart failure risks associated with DPP-4 inhibitors, Zannad and Rossignol point out that, when looked at overall, the heart failure descriptors used in the trials conducted so far are "weak" and the outcome definitions used "are both inconsistent and heterogeneous."

"Therefore, it is no surprise that some of these trials raise more questions than they offer definitive answers regarding heart failure outcomes," they write.

But there are currently "no known mechanisms that would explain an increased heart failure risk with DPP-4 inhibition," they say, and patients in the SAVOR-TIMI 53 trial did not have increases in risk factors associated with heart failure.

"The bottomline is that there is no plausible mechanism offered to explain the unexpected findings of SAVOR-TIMI 53."

Zannad and Rossignol say that the accumulated data from the DPP-4 inhibitor trials suggest that "the most likely explanation" is "an initial chance finding" and that the drugs "most likely have neutral effects on cardiovascular outcomes overall, including heart failure outcomes."

Best Choice for Those With or at Risk of Heart Failure Is SGLT2 Inhibitor

However, they continue, "For the sake of extreme caution, and the benefit of the doubt, if one is to use a DPP-4 inhibitor, it may be fair to avoid saxagliptin in patients with or at risk of heart failure, given that all other [DPP-4 inhibitor] drugs have no heart failure issue, whether true or perceived.

Zannad and Rossignol nevertheless believe that the "appropriate choice as an alternative to DPP-4 inhibition" in patients with or at low risk of heart failure "should now be" a sodium-glucose cotransporter 2 (SGLT2) inhibitor, such as empagliflozin or canagliflozin, based on the EMPA-REG and CANVAS trials.

This was reinforced by new data from the DECLARE TIMI 58 trial, in which more than 17,000 patients with type 2 diabetes, of whom 10,000 were free from cardiovascular disease at baseline, were randomized to another SGLT2 inhibitor, dapagliflozin (Farxiga/Forxiga, AstraZeneca), or placebo in addition to standard care.

The results, which were also reported at the American Heart Association (AHA) Scientific Sessions 2018, show dapagliflozin was associated with a significant reduction in hospitalizations for heart failure, alongside a nonsignificant trend towards a reduced rate of major adverse cardiac events.

Presenting the DECLARE findings at AHA, Stephen Wiviott, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, said, "I think after the DECLARE-TIMI 58 trial we can definitely now say the biggest benefit of the SGLT2 inhibitors is the prevention of heart failure."

No Significant Differences in Heart Failure Hospitalizations

For the current secondary analysis of CARMELINA, McGuire and colleagues examined data on heart failure hospitalizations, cardiovascular outcomes, and deaths, which had been prospectively gathered and then centrally adjudicated from the 6979 patients with type 2 diabetes from 27 countries who were in the trial.

The linagliptin and placebo groups were well balanced in terms of their baseline characteristics, and both sets of patients had relatively well-controlled blood pressure, lipids, and glycemic indices.

Over a mean follow-up of 2.2 years, 435 patients had at least one heart failure hospitalization.

Cox proportional analysis indicated that there was no significant difference in the incidence of heart failure hospitalization between patients treated with linagliptin and those given placebo, at 6.0% versus 6.5%, or a hazard ratio of 0.90 (P = .26).

In addition, there was no difference between the two treatment groups in terms of the composition endpoint of cardiovascular death or heart failure hospitalization, at a hazard ratio of 0.94 (P = .39).

The team also notes that linagliptin was not associated with an increase in the risk of first or recurrent heart failure hospitalization versus placebo, at a hazard ratio of 0.94 (P = .63).

McGuire and colleagues conducted further analyses to determine the impact of heart failure hospitalization history at baseline, baseline estimated glomerular filtration rate, and urine albumin-creatinine ratio, and found no signs of heterogeneity.

The patients were also stratified depending on whether they had a pre-randomization left ventricular ejection fraction of > 50% or ≤ 50%, which had no effect on the results either.

They did, however, "observe statistical heterogeneity of the effect of linagliptin on heart failure hospitalization by region, by baseline insulin use, and, not consistently, by baseline blood pressure."

While noting that these results are "hypothesis generating" they acknowledge that "because of the large number of subgroup analyses conducted, we cannot exclude that these interactions may be spurious."

The research was supported by the Boehringer Ingelheim and Eli Lilly Diabetes Alliance. McGuire has received personal fees from Boehringer Ingelheim, Janssen, Sanofi-Aventis, Genentech, MSD, Daiichi Sankyo, Lilly, Novo Nordisk, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Lexicon, Eisai Janssen, Merck, Pfizer, Metavant, and Applied Therapeutics. Disclosures for the other authors and editorialists are listed with the articles.

Circulation. Published online November 11, 2018. Abstract

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