DPP-4 inhibitors and cardiovascular outcomes

New Engl J of Med just had a large study on the cardiovascular effects of sitagliptin (see dm sitagliptin cardiovasc nejm 2015 in dropbox, or 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 sitagliptin100mg/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%) withsitiigliptin 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 anyprespecified 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 (baselineA1c, 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 longterminsulin

                --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….