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Is the Use of DPP-4 Inhibitors Associated with an Increased Risk for Heart Failure?

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Is the Use of DPP-4 Inhibitors Associated with an Increased Risk for Heart Failure? S210 Diabetes Care Volume 39, Supplement 2, August 2016 Is the Use of DPP-4 Inhibitors Guntram Schernthaner,1 Avivit Cahn,2 and Itamar Raz2 RECENT OUTCOME STUDIES Associated With an Increased Risk for Heart Failure? Lessons From EXAMINE, SAVOR-TIMI 53, and TECOS Diabetes Care 2016;39(Suppl. 2):S210–S218 | DOI: 10.2337/dcS15-3009 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 Di- abetes 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 cardio- myopathy, and extracellular fluid volume expansion (4,5). Remarkably, type 2 di- abetes itself is a recognized risk factor for HF, independent of CAD and hypertension (4), suggesting that glycemic control may influence the development of HF. Hyper- glycemia can exert deleterious effects on the myocardium and has been shown to increase oxidative stress, promote accumulation of advanced glycation end prod- ucts, and cause interstitial fibrosis (6). Hyperglycemia has also been associated with myocardial lipotoxicity, mitochondrial dysfunction, abnormal substrate metabo- lism, 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 for HF of 1.15 (95% CI 1.10–1.21) for each percent (point higher) increase of HbA1c. In a recent Scottish study (10), 8% of 8,683 patients with type 2 diabetes developed HF during a 5.5-year follow-up, andbothlowHbA1c, ,6% (hazard ratio [HR] 1.60 [95% CI 1.38–1.86]; P , 0.0001), and high HbA1c, .10% (1.80 [1.60–2.16]; P , 0.0001), were independently associated with the risk of HF. 1Department of Medicine I, Rudolfstiftung Hos- Owing to the significant contribution of diabetes to the pathogenesis of HF, the pital, Vienna, Austria 2 effect of the various antihyperglycemic agents on HF must be assessed and balanced Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel with their benefit in glucose reduction (11–13). Thiazolidinediones may cause HF, the main mechanism being fluid retention (13), and are generally contraindicated in Corresponding author: Guntram Schernthaner, [email protected]. patients with New York Heart Association (NYHA) class III–IV HF (14). Insulin has This publication is based on the presentations been associated with an increased risk of HF in several studies (15), though in the at the 5th World Congress on Controversies to Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial no such signal Consensus in Diabetes, Obesity and Hyperten- was observed (16). A study that assessed the association of antidiabetes medica- sion (CODHy). The Congress and the publication tions with the risk of hospitalization for HF showed inferiority of sulfonylurea or of this supplement were made possible in insulin to metformin therapy (17). Metformin is now considered the safest thera- part by unrestricted educational grants from AstraZeneca. peutic alternative for individuals with HF (18). A recently published cardiovascular fl © 2016 by the American Diabetes Association. (CV) outcome study with empagli ozin demonstrated a 35% relative risk (RR) re- Readers may use this article as long as the work is duction of hospitalization for HF with the drug versus placebo (19), and it remains to properly cited, the use is educational and not for be seen whether this effect exists in additional drugs in the class. profit, and the work is not altered. care.diabetesjournals.org Schernthaner, Cahn, and Raz S211 The glucagon-like peptide 1 receptor variables to some extent; however, it in comparison with those treated with agonist lixisenatide has demonstrated in cannot fully correct for significant placebo or other active comparators its recently presented randomized con- baseline differences in the population. (odds ratio 1.19 [95% CI 1.03–1.37]; trolled trial (RCT) no increase in the risk Since the prescription patterns are re- P = 0.015). When SAVOR-TIMI 53 (22) of hospitalization for HF versus placebo lated to disease severity and often to and EXAMINE (23), which accounted (20). socioeconomic status, the outcomes for the majority of the overall result, Dipeptidyl peptidase (DPP)-4 inhibi- are thus related to the variable stud- were removed from the analysis, no sig- tors are extensively used in the treat- ied, which is a major confounder not nal of risk was detectable in the other ment of diabetes and were prescribed easily overcome even by multivariable trials, which were designed for non-CV in 21% of treatment visits in the U.S. in adjustment. Additionally, as these are outcomes. The meta-analysis of Savarese 2012 (21). The effect of DPP-4 inhibitors not randomized data, residual confound- et al. (33), analyzing 94 trials enrolling on the risk for hospitalization for HF has ing may remain unadjusted for due to ei- 85,224 patients, arrived at similar re- been extensively discussed in several ther the lack of data or confounders that sults. Compared with control subjects, observational studies and meta-analyses. were not considered. treatment with DPP-4 inhibitors did not The publication of three randomized affect all-cause or CV mortality or stroke, controlled trials of CV outcomes with DPP-4 Inhibitors and HF: Evidence but long-term treatment with DPP-4 in- saxagliptin (22) and alogliptin (23) and From Meta-analyses hibitors was associated with a 15.8% in- most recently with sitagliptin (24) versus Wu et al. (30) analyzed 50 trials compar- creased risk of hospitalization for HF (RR placebo revealed contradictory results ing DPP-4 inhibitors with comparators 1.158 [95% CI 1.011–1.326]; P = 0.034). that merit renewed discussion regarding (placebo or active comparator) enrolling No heterogeneity among studies or pub- the potential association between the 55,141 participants; however, mean lication bias was detected. use of DPP-4 inhibitors and HF. follow-up was only 45.3 weeks. Treat- A meta-analysis, which included ment with DPP-4 inhibitors compared .17,000 patients in the development DPP-4 Inhibitors and HF: Evidence with placebo showed no increase in risk program of vildagliptin (phase III and From Observational Studies with regard to all-cause mortality, CV IV studies), assessed the CV safety and Several observational studies have at- mortality, acute coronary syndrome, or HF profile of vildagliptin. The analysis temptedtoassesstheassociationbe- stroke but a statistically significant in- included 9,599 patients receiving vilda- tween the use of DPP-4 inhibitors and creased risk of hospitalization for HF gliptin and 7,847 subjects receiving pla- hospitalization for HF (25–29) (Table 1). outcomes (n = 39,953) (RR 1.16 [95% cebo in trials with a median duration of The studies have generally used pro- CI 1.01–1.33]; P = 0.04) (Fig. 1). This nearly 1 year. CV events were adjudicated pensity score matching, with varying meta-analysis was mainly influenced by an independent committee in a pre- success at matching the groups, and by the SAVOR-TIMI 53 (Saxagliptin planned fashion as secondary end points applied a Cox proportional hazards Assessment of Vascular Outcomes of these trials. Confirmed HF events were model or a conditional logistic regres- Recorded in Patients with Diabetes reported in 41 patients in the vildagliptin sion to adjust for further confounding. Mellitus–Thrombolysis in Myocardial In- group (0.43%) and in 32 patients in the These studies demonstrate conflicting farction 53) trial (22), contributing 66.2% of comparator group (0.45%) (RR 1.08 [95% results, with some pointing to a poten- the weight in the analysis, with EXAMINE CI 0.68–1.70]) (34). tial hazard associated with the use of DPP- (Examination of Cardiovascular Out- Meta-analyses of studies from the 4 inhibitors (25,26), others demonstrating comes with Alogliptin versus Standard development programs of linagliptin, a neutral effect (28,29), and one showing a of Care) (23) contributing 21.3% and sitagliptin, and alogliptin, which as- possible benefit associated with the use of the VIVIDD (Vildagliptin in Ventricular sessed the incidence of major adverse DPP-4 inhibitorsdin those with no base- Dysfunction Diabetes) (31) trialscontribut- CV events (MACEs), did not include line CV disease [CVD]dcompared with the ing 6.9%. The results were similar compared HF events (35–37). (In the alogliptin use of sulfonylureas (27). with a placebo comparator (n = 27,818) (RR study, HF events were collected as Observational studies are generally 1.17 [95% CI 1.01–1.34]; P =0.03)and part of the “adjudicated serious non- limited by missing data; e.g., in the were not significant compared with the MACE CV events” [37].) A meta-analysis studybyGiordaetal.(29)nodatare- active comparator (n = 12,563) (0.80 from the development program of garding metabolic control, blood pres- [0.35–1.81]; P = 0.59).
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