Is the Use of DPP-4 Inhibitors Associated With an Increased Risk for Heart Failure? Lessons From EXAMINE, SAVOR-TIMI 53, and TECOS

About 40 years ago, the Framingham study first documented that the risk for heart failure (HF) in patients with diabetes was about twofold higher in men and fivefold in women compared with individuals without diabetes (1). The UK Prospective Diabetes Study (UKPDS) reported that the incidence of hospital admission for HF was similar to that of nonfatal myocardial infarction and nonfatal stroke (2). A more recent 6-year follow-up study of 65,619 patients with type 2 diabetes treated with insulin reported that the hospital admission rate due to HF (243 of 10,000) was higher than that due to myocardial infarction (97 of 10,000) or stroke (151 of 10,000) (3). The pathogenesis of HF in diabetes is multifactorial but can largely be attributed to four key factors: coronary artery disease (CAD), hypertension, diabetic cardiomyopathy, and extracellular fluid volume expansion (4,5). Remarkably, type 2 diabetes itself is a recognized risk factor for HF, independent of CAD and hypertension (4), suggesting that glycemic control may influence the development of HF. Hyperglycemia can exert deleterious effects on the myocardium and has been shown to increase oxidative stress, promote accumulation of advanced glycation end products, and cause interstitial fibrosis (6). Hyperglycemia has also been associated with myocardial lipotoxicity, mitochondrial dysfunction, abnormal substrate metabolism, and impaired calcium handling (7). Epidemiological evidence indicates that HbA1c and the risk of HF are significantly related. A cohort study of ∼49,000 patients with type 2 diabetes showed that each 1% increase in HbA1c was associated with an 8% increased risk of HF and that an HbA1c ≥10 relative to HbA1c <7 was associated with 1.56-fold (95% CI 1.26–1.93) greater risk of HF (8). A more recent meta-analysis (9) of 178,929 subjects with diabetes and 14,176 incident chronic HF cases showed an overall adjusted risk ratio …