diabetes DPP-4 inhibitors and the risk of heart failure

the FDA just came out with a safety alert about 2 DPP-4 inhibitors and the increased risk of heart failure (released 04/05/2016)(see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494252.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery​ ). details:

--saxagliptin and alogliptin were singled out because of 2 clinical trials in diabetic patients with heart disease. in each trial more patients taking these meds were hospitalized for heart failure vs those on placebo

    --in the saxagliptin trial: 3.5% were hospitalized for heart failure (vs 2.8% on placebo). risk factors included prior heart failure or kidney disease

    --in the alogliptin trial: 3.9% were hospitalized for heart failure (vs 3.3% on placebo)

--recommendation by the FDA:

    --we should consider stopping these drugs if the patient develops heart failure

--i believe these trials (not cited specifically by the FDA) were the ones in the blog http://blogs.bmj.com/ebm/2013/09/10/primary-care-corner-with-geoffrey-modest-md-new-diabetes-drugs-dpp-4-is-lower-a1c-not-cardiac-events/​ . the saxagliptin one was clearly the one in the blog, the alogliptin one probably was (reviewing the article, they did not have any breakdown for developing heart failure in the article or the supplementary materials. my guess is that the FDA got their hands on more specific data....)

ironically, this FDA safety alert was published 2 weeks after the new england journal of medicine published a multicenter observational study of these meds and heart failure (N Engl J Med 2016;374:1145), looking at health care data from Canada, UK, and the US, using a nested case-control design (matching each heart failure case to 20 controls from the same cohort), finding:
--1,499,650 patients involved, 29,741 hospitalized for heart failure
    --for those without history of heart failure: HR 0.86 (0.62-1.19)
    --for those with history of heart failure: HR 0.82 (0.67-1.00)
    ​--no difference between those on DPP-4 inhibitors or GLP-1 agonists

so, how does this affect us?

--as i have mentioned many times in the past, i do not see any big benefit from using these drugs: the A1C benefit is not very large (about 0.3% in several studies, including the above 2 studies as well as the sitigliptin one in the additional blog below), DPP-4 is a pretty ubiquitous enzyme which deactivates lots of different bioactive peptides (ie, DPP-4 inhibitors are hardly magic bullets), and it is really not so surprising that there may be significant collateral damage. 

--the pretty small absolute increases in hospitalizations for heart failure (0.6-0.7%) is likely the tip of the iceberg. diabetics get lots of heart disease (the vast majority of diabetics, in the 70-80% range, die from heart disease), most heart failure (i think) is treated as an outpatient and therefore not showing up in statistics for hospitalizations, and the mortality from heart failure may well be higher in patients not enrolled in a study, where study personnel tend to follow patients closely and patients have easy access to them (this may be especially true in areas of the country where there is not ready access to any high quality outpatient care or hospitals.) 

--since so many diabetic patients develop heart failure just because of their diabetes and other risk factors, i think it is important that the FDA brings this drug association to our attention (ie, one would not think necessarily that the drug caused the heart failure). not exactly sure what to do with the recent NEJM article, though it was a retrospective matching of patients from many trials (albeit a pretty big one)

--so, the DPP-4 inhibitors are not on my list of meds to use, even in patients without known underlying heart or kidney disease..... [though, i should add, that i do use GLP-1 agonists, which have a much more dramatic effect on A1C levels, are more physiologic than exogenous insulin or sulfonylureas, and are very specifically targeted to meal-related endogenous insulin release (the "incretin" effect).  so, though it might surprise you, i am really not against all new drugs...]

http://gmodestmedblogs.blogspot.com/2015/06/dpp-4-inhibitors-and-cardiovascular.html/ ,which looks at sitigliptin (not one of the ones singled out by the FDA), showing very small effects on A1C levels, showing no increase in cardiovascular outcomes, but does bring up the point that for the minimal-effect on A1c, DPP-4 inhibitors block a ubiquitous enzyme on the surface of most cells and deactivates a variety of bioactive peptides