By: Dr. Geoffrey Modest
New Engl J of Med just had a large study on the cardiovascular effects of sitagliptin (see DOI: 10.1056/NEJMoa1501352). Background: sitigliptin is a DPP-4 inhibitor (dipeptidyl peptidase 4 inhibitor), which functions by decreasing the degradation of incretins (and thereby increasing glucose-mediated endogenous insulin secretion and suppressing glucagon levels). But there were concerning studies with other DPP-4 inhibitors being associated with increased risk of hospitalization for heart failure (saxagliptin was associated with 27% increase in the SAVOR-TIMI study, aloglipitin with a nonstatistically significant increase in EXAMINE study).
Details of the new study (drug company sponsored):
–14,671 patients from 673 sites in 38 countries were randomized to adding sitagliptin 100mg/d (50mg if eGFR 30-50) vs placebo to existing therapy. Followed 3 years
–median age 66, 30% female, 68% white/22% asian/12% latino, BMI 30, BP 135/77, eGFR 75, prior MI 43%, 11% current smoker, LDL 91 mg/dl
— results:
–26% of each group discontinued the med or placebo during the study
–at 4 months there was a 0.4% lowering of A1c (from baseline of 7.3%) with sitiigliptin compared with placebo. By 3 years, there was only a 0.29% difference
–but, during the course of the study, those of sitigliptin were less likely to start long-term insulin therapy (9.7% in those on sitigliptin vs 13.2% on placebo [HR 0.70 (0.63-0.79)]).
–primary outcome (composite of cardiovasc death, nonfatal MI, nonfatal stroke, hospitalization for heart failure): 11.4% in those on sitagliptin and 11.6% on placebo, not significantly different
–for the various secondary outcomes (which include the individual components of the primary outcome and more): no difference. Also, no difference by any prespecified subgroups (age, sex, race, region of the world, diabetes duration, baseline diabetes therapy, high vs low A1c, BMI, smoking)
–no difference in hospitalization for heart failure
–no difference in adverse events (though the rate of acute pancreatitis came close to being significant, with 23 cases in those on sitaglipitin and 12 in placebo, p=0.07. Pancreatitis has been found to be increased in several of the DPP-4 agents). No difference in pancreatic cancers (though only 3 year study). There was, however, a statistically significant decrease in eGFR with sitigliptin of -4.0 vs -2.8 ml/minm/1.73m2.
So, what does this study show? First, this was a very select group of patients (baseline A1c, hypertension, cholesterol very well controlled). They excluded those with significant renal dysfunction (eGFR<30). And…
The good news:
–there was some benefit from sitigliptin in reducing the need for longterm insulin
–there was no increase in cardiac events individually, and there was no increase in hospitalizations for heart failure
The bad news:
–the difference in A1c with sitigliptin was really pretty small, with people improving their control with other meds (which may explain the lack of benefit from using sitiglipitin)
–there was no cardiac protection by sitigliptin (which is really the most important endpoint, since 70-80% of diabetics die of cardiovasc disease, an order of magnitude greater than mortality from microvascular complications)
My bottom line: I have never used DPP-4 inhibitors because they are expensive, they require prior authorizations, they have very small effects on A1C (typically about 0.5%), and they have no documented benefit on actual clinical outcomes (and the decrease in eGFR may presage a worsening of this important microvascular outcome). I also have a baseline unease with medications that block a ubiquitous enzyme (DPP-4) which is on the surface of most cells and deactivates a variety of bioactive peptides, not just GIP (glucose-dependent insulinotropic polypetide) and GLP-1 (glucagon-like peptide-1). So, I basically plan to continue with my pattern of not using them….