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Diabetes, Cardio-Metabolic Newsletter
Update DPP-4 Inh. And CHF
7/14/2014
Data from Diabetic Patients Initially With HF [from Medscape)
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."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.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." MY COMMENTARY-
FOR NOW , I WOULD AVOID DPP-4 INH in patients with CHF, a la pioglitazone- may be related to other proteins
in serum not degraded by DPP-4 as usual, which then increase CHF risk. This is despite logic referred to above that
suggests that GLP-1 effect might reduce CHF risk- ie I will continue to use GLP-1 RAs in CHF