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

Abstract

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 HbA 1c 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 HbA 1c was associated with an 8% increased risk of HF and that an HbA 1c $10 relative to HbA 1c ,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 for HF of 1.15 (95% CI 1.10-1.21) for each percent (point higher) increase of HbA 1c . In a recent Scottish study (10), 8% of 8,683 patients with type 2 diabetes developed HF during a 5.5-year follow-up, and both low HbA 1c , ,6% (hazard ratio [HR] 1.60 [95% CI 1.38-1.86]; P , 0.0001), and high HbA 1c , .10% (1.80 [1.60-2.16]; P , 0.0001), were independently associated with the risk of HF.

Plasma dipeptidyl-peptidase-4 activity is associated with left ventricular systolic function in patients with ST-segment elevation myocardial infarction

“…However, in another large RCT, the TECOS study, sitagliptin did not increase the rate of hospitalization for HF in T2DM patients with established cardiovascular disease: HR 1.00 (95% CI: 0.83–1.20) 26 . In a small RCT, the VIVIDD Trial, vildagliptin usage in T2DM patients with established HF did not worsen HF 21 . A recent meta-analysis showed that there is only weak evidence for an increased risk of HF with gliptin usage 27 .…”

“…In the SAVOR-TIMI 53 study, saxagliptin usage was associated with decreased NT-proBNP levels (4 vs. 10 pg/mL in the placebo group; p  = 0.001) 20 . In the VIVIDD Trial, diabetic patients taking vildagliptin had lower BNP levels (28 vs. 14% in the placebo group) relative to baseline at 52 weeks 21 . On the other hand, acute treatment with linagliptin does not alter the plasma concentration of BNP and NT-proBNP.…”

Novel oral glucose‐lowering drugs are associated with lower risk of all‐cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes

“…Notwithstanding these reassuring results, some concerns have been raised regarding adverse events from the novel drugs, such as heart failure and pancreatitis for the DPP‐4 inhibitors, and sporadic cases of ketoacidosis for SGLT2 inhibitors . The relationship of DPP‐4 inhibitors with increased risks of hospitalization for heart failure has not yet been resolved; however, the results of another observational study and a meta‐analysis are not consistent with this finding …”

“…19,36 The beneficial associations of lowered CVD and mortality risks in the present study should also be interpreted in the context of a T2D population with a lower CVD burden at baseline compared with the clinical randomized trial. 17 Notwithstanding these reassuring results, some concerns have been raised regarding adverse events from the novel drugs, such as heart failure 44 and pancreatitis for the DPP-4 inhibitors, 45 and sporadic cases of ketoacidosis for SGLT2 inhibitors. 46 The relationship of DPP-4 inhibitors with increased risks of hospitalization for heart failure has not yet been resolved; however, the results of another observational study and a meta-analysis are not consistent with this finding.…”

“…46 The relationship of DPP-4 inhibitors with increased risks of hospitalization for heart failure has not yet been resolved; however, the results of another observational study and a meta-analysis are not consistent with this finding. 31,44 A strength of the present work is the population-based, nationwide and unselected real-world study design, which provides a high external validity and large population, allowing propensity scorematched analyses. In addition, this is a study with full register coverage for hospitalizations, filled drug prescriptions, and cause of death in a country with an established and complete public healthcare system.…”