{"id":750,"date":"2015-06-24T11:00:29","date_gmt":"2015-06-24T11:00:29","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=750"},"modified":"2017-08-21T11:47:02","modified_gmt":"2017-08-21T11:47:02","slug":"primary-care-corner-with-geoffrey-modest-md-dpp-4-inhibitors-and-cardiovascular-outcomes","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/06\/24\/primary-care-corner-with-geoffrey-modest-md-dpp-4-inhibitors-and-cardiovascular-outcomes\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: DPP-4 inhibitors and cardiovascular outcomes"},"content":{"rendered":"

By:\u00a0 Dr. Geoffrey Modest<\/strong><\/p>\n

New Engl J of Med just had a large study on the cardiovascular effects of sitagliptin (see\u00a0DOI: 10.1056\/NEJMoa1501352<\/strong>). 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\u00a0nonstatistically significant increase in EXAMINE study).<\/p>\n

\"Untitled\"<\/a><\/p>\n

Details of the new study (drug company sponsored):<\/p>\n

–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<\/p>\n

–median age 66, 30% female, 68% white\/22% asian\/12% latino, BMI 30, BP 135\/77, eGFR 75, prior MI 43%,\u00a011%\u00a0current smoker, LDL 91 mg\/dl<\/p>\n

— results:<\/p>\n

–26% of each group discontinued the med or placebo during the study<\/p>\n

–at 4 months there was a 0.4% lowering of A1c (from baseline of 7.3%) with sitiigliptin compared \u00a0with placebo. By 3 years, there was only a 0.29% difference<\/p>\n

–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\u00a013.2% on placebo [HR 0.70 (0.63-0.79)]).<\/p>\n

–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,\u00a0not significantly different<\/p>\n

–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)<\/p>\n

–no difference in hospitalization for heart failure<\/p>\n

–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\u00a0in 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\u00a0 with sitigliptin of -4.0 vs -2.8 ml\/minm\/1.73m2<\/sup>.<\/p>\n

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…<\/p>\n

The good news:<\/p>\n

–there was some benefit from sitigliptin in reducing the need for longterm insulin<\/p>\n

–there was no increase in cardiac events individually, and\u00a0there was no \u00a0increase in hospitalizations for heart failure<\/p>\n

The bad news:<\/p>\n

–the difference in A1c with sitigliptin was really\u00a0pretty small, with\u00a0people improving their control with other meds (which may explain the lack of benefit from using sitiglipitin)<\/p>\n

–there was no cardiac protection by sitigliptin (which is really\u00a0the most important endpoint, since 70-80% of diabetics die of cardiovasc disease, an order of magnitude greater than mortality from microvascular complications)\u200b<\/p>\n

\u00a0My 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\u00a0microvascular 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). \u00a0So, I basically plan to continue with my pattern of not using them\u2026.<\/p>\n

 <\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

By:\u00a0 Dr. Geoffrey Modest New Engl J of Med just had a large study on the cardiovascular effects of sitagliptin (see\u00a0DOI: 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 […]<\/p>\n

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