The Sitagliptin Saga: More Evidence for Possible HF Hazard

July 03, 2014

EDMONTON, AB — Signals of a possible heart-failure (HF) hazard from second-line treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes seen in recent randomized and observational studies have risen a few decibels[1]. An analysis of patient-level data from nationwide US insurance records saw initiation of sitagliptin (Januvia, Merck), one the most commonly used DPP-4 inhibitors, pose an 84% increased risk (p=0.01) of new HF hospitalization among diabetic patients initially with HF who had been treated with metformin or a sulfonylurea. The more than 7600 patients in the cohort had been followed a median of 1.4 years.

Sitagliptin therapy showed no sign of increasing risk for all-cause hospitalization or death, which was the primary end point of the study, published July 2, 2014 in Circulation: Heart Failure by first author Daniala L Weir (University of Alberta, Edmonton) and colleagues.

As in prior analyses hinting at similar risks from DPP-4 inhibitors, in which only some diabetic patients already had HF when the drugs were started, HF hospitalization was a secondary end point while primary-end=point outcomes for DPP-4 inhibition were, in contrast, often favorable or neutral.

The increased HF risk in the current analysis "is likely clinically relevant," according to the authors, with an observed number needed to harm of 29, "and may have implications for choice of add-on therapy for patients with HF and diabetes poorly controlled with other agents."

They continue, "Although our results are intriguing, it is clear that additional studies are required, specifically in patients with HF, to solidify the risk/benefit picture," especially given "inconsistent" evidence from clinical trials regarding any HF risk from DPP-4 inhibitors.

Recent Causes for Concern

The randomized SAVOR-TIMI 53 trial of saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) showed a significant 27% increased risk of HF hospitalization in 16 492 diabetic patients with a CV history or otherwise at elevated CV risk. That was despite saxagliptin noninferiority for the primary end point of CV death, nonfatal MI, or nonfatal ischemic stroke vs placebo.

And the 5380-patient Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial of alogliptin (Nesina, Takeda Pharmaceuticals) showed a nonsignificant trend suggesting more HF in diabetic patients taking the DPP-4 inhibitor. Both studies had been reported by heartwire .

On the other hand, a recent unpublished post hoc analysis of the much smaller Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD), which focused on echocardiographic rather than clinical end points, found no elevated risk of HF hospitalizations or other HF events in diabetic patients with HF who received vildagliptin (Galvus, Novartis).

Two observational studies presented recently at the International Society of Endocrinology and the Endocrine Society joint scientific sessions, and covered by Medscape Medical News, gave somewhat conflicting results regarding DPP-4-inhibitor use and HF outcomes. One retrospective study of 13 185 outpatients with diabetes on metformin showed a significantly elevated HF risk over four years among those also taking a DPP-4 inhibitor compared with a different second-tier antidiabetic agent. And in the other study, a cohort of 32 419 matched pairs of patients with diabetes taking or not taking a DPP-4 inhibitor, DPP-4 inhibitors were not associated with an increased risk of CV events and may have even improved HF overall.

Data from Diabetic Patients Initially With HF

The analysis of 7620 diabetic patients and HF (58% male) treated with metformin or a sulfonylurea but not a thiazolidinedione included 887 patients who started on sitagliptin sometime after their HF diagnosis.

In an adjusted analysis, there were no differences between sitagliptin users and nonusers for the primary end point of all-cause hospitalization or death, the secondary end point of HF hospitalization or death from any cause, or all-cause death or all-cause hospitalization by themselves. However, HF admissions went up significantly with sitagliptin.

In addition, treatment with metformin was associated with a 22% reduced adjusted risk of the primary end point (p<0.001), whereas that end point was raised 10% for users of sulfonylureas (p=0.043) and 16% for users of insulin (p=0.004).

"Before recent studies, there was little evidence, either clinical or basic science, to suggest DPP-4 inhibition would increase the risk of heart failure," write Drs Deepak L Bhatt and Matthew A Cavender (Brigham and Women's Hospital, Boston, MA) in an accompanying editorial[2].

"In contrast, basic science data largely suggested that DPP-4 inhibition should improve cardiovascular events, including ventricular function," they continue, noting the confusing state of the evidence so far.

"The findings of this analysis, as well as other recent studies, highlight the need for well-designed trials that rigorously assess for HF in patients with diabetes. The ongoing . . .  Trial Evaluating Cardiovascular Outcomes with Sitagliptin [TECOS] has randomized approximately 14 000 patients with type 2 diabetes [and preexisting CVD] to sitagliptin or placebo, and it may help establish whether the class of DPP-4 inhibitors does indeed cause HF."

Adjusted* Odds Ratio (95% CI), Exposure vs No Exposure to Sitagliptin and Metformin in Diabetic Patients With HF

End points Sitagliptin OR (95% CI), p Metformin OR (95% CI), p
All-cause death or hospitalization 0.84 (0.69–1.03), 0.10 0.78 (0.71–0.85), <0.001
All-cause death 1.16 (0.68–1.97), 0.59 0.52 (0.37–0.71), <0.001
All-cause hospitalization 0.93 (0.76–1.14), 0.46 0.79 (0.71–0.87), <0.001
HF-related hospitalization or death 1.34 (0.93–1.92), 0.12 0.70 (0.57–0.86), 0.001
HF-related hospitalization 1.84 (1.16–2.92), 0.01 0.87 (0.66–1.12), 0.28
*Adjusted for age and sex; type of medical insurance; household income; recent glycosylated hemoglobin, low- and high-density lipoprotein cholesterol, triglycerides, and estimated glomerular filtration rate; history of CVD; antidiabetic drug therapies; CV drug therapies
CI=confidence interval
OR=odds ratio

The trial's primary end point is "time to first confirmed CV event (a composite defined as CV-related death, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization)." Time to congestive HF is a TECOS secondary end point.

According to Weir et al, although the ongoing DPP-4 inhibitor trial as well as the earlier ones "enrolled patients with established cardiovascular disease or risk factors, none specifically identified individuals with established heart failure. Therefore, it is unlikely the upcoming results of the TECOS trial will provide evidence for the safety of sitagliptin therapy in those with preexisting HF, unless evaluated as a subgroup."

Weir had no industry-related disclosures. Disclosures for the coauthors are listed in the paper. Bhatt disclosed being a member of advisory boards for Medscape Cardiology Education and Regado Biosciences; receiving honoraria from CardioSource, WebMD (parent company of theheart.org/Medscape Cardiology); receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi, and the Medicines Company; conducting unfunded research with FlowCo, PLx Pharma, and Takeda; and being co–principal investigator of the SAVOR-TIMI 53 trial, funded by AstraZeneca and Bristol-Myers Squibb. Cavender was a coinvestigator in SAVOR-TIMI 53.

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