Beta-blockade with Bisoprolol Linked with Higher Mortality Benefits in Heart Failure Patients with Diabetes
Introduction
Type 2 diabetes (T2DM) is a common comorbidity in heart failure and seen in over one-third patients with HF. The comorbid association of T2DM with HF with reduced ejection fraction (HFrEF) confers prognostic disadvantages to the affected patients. Of note, HFrEF patients with T2DM demonstrated a three-fold higher risk of mortality than that in HFrEF patients without T2DM.
Bisoprolol, a cardio-selective once-daily beta-blocker, is used as a disease-modifying therapy in patients with HFrEF. In addition, bisoprolol has been shown to confer HFrEF patients with mortality benefits. However, the mortality benefits of bisoprolol in the subset of HFrEF patients with T2DM have not been prospectively demonstrated. In addition, the incremental mortality benefits due to dose escalation of bisoprolol in these comorbid patients have not been examined previously.
Aims
This prospective analysis by Witte et al.1 on a cohort of patients with HFrEF treated with beta-blockade, mainly bisoprolol, aimed to compare the all-cause mortality in the subgroups of HFrEF patients with and without T2DM. In addition, this cohort study also aimed to evaluate the relationship between incremental doses of bisoprolol and mortality benefits in HFrEF patients with and without T2DM, expecting them to be different.
Methods
This prospective cohort study was conducted in 1,797 British patients with HFrEF (ejection fraction <45 on transthoracic echocardiography). Only the stable adult consecutive patients with HFrEF of over 3-months duration who attended one of four earmarked cardiology clinics in Leeds, United Kingdom between June 2006 and December 2014 were enrolled in this study. Patient were followed-up until May 2016 or death.
The clinical data were collected in accordance with the internationally established scientific standards. Data on beta-blockers, renin-angiotensin system inhibitors (RASIs) and loop diuretics were expressed in terms of equivalent doses of bisoprolol, ramipril, and furosemide, respectively when agents different from these were used in the patients. Bisoprolol use was characterized as low-dose: <2.5 mg per day; medium dose: 2.5-7.4 mg per day; and high-dose: ≥ 7.5 mg per day.
Between-group survivals were compared via Kaplan-Meier curves and log-rank tests, or via Cox proportional hazards regression analyses. Statistical significance was set at p <0.05. This study received ethical approval from The Leeds West Research Ethics Committee and was conducted according to the principles of the Declaration of Helsinki.
Results
The mean follow-up duration in this study was four years with a total follow-up of 7,227 patient years. Of the 1,797 included participants 503 (28%) had diabetes, mainly T2DM (497/503), while 1,294 participants did not. The mean baseline HbA1C of diabetic participants was 7.8.
Participants with T2DM had lower baseline hemoglobin and glomerular filtration rate. They were more likely to have NYHA III/IV disease but had less-impaired left ventricular function. They received higher doses of bisoprolol, ramipril, and furosemide. There were 494 deaths in patients without diabetes and 241 in patients with diabetes.
Among the 1,797 participants, 1,523 received beta-blockers, of which 1,276 (83.8%) received bisoprolol; while carvedilol and metoprolol were used in 10.8% and 5.4% of beta-blockers users, respectively. Beta-blocker use was similar between diabetic and non-diabetic HFrEF patients.
The all-cause mortality was inversely associated with bisoprolol dosage in both diabetic and non-diabetic HFrEF patients, and the lowest all-cause mortality was observed in patients receiving bisoprolol dose of ≥ 7.5 mg per day (Figure 1; red line denotes the curve for patients receiving of ≥ 7.5 mg bisoprolol per day).
Figure 1.Kaplan-Meier curves for all-cause mortality in HFrEF patients without and with diabetes.1
However, the inverse association of all-cause mortality with bisoprolol dosage was more prominent in HFrEF patients with T2DM as shown in Figure 1. Furthermore, this association was also demonstrated in the Cox proportional hazards regression analysis (8.9% vs. 3.5% mortality reduction for each milligram per day increment in diabetics and non-diabetics, respectively; p=0.027). This significant association persisted even when adjusted for age, sex, ramipril dose, disease severity and presence of an implantable cardioverter-defibrillator but lost significance (p=0.086) when heart rate was also adjusted.
Additional subgroup analyses were conducted in HFrEF patients with T2DM based on ejection fraction, glycemic control, and insulin treatment (Figure 2). As can be noted from Figure 2, of these three only the ejection fraction had a significant interaction based on a cut-off of EF value of 32.
Figure 2. Significant interaction for ejection fraction.1
Discussion and Conclusions
The authors argued that unlike previous retrospective analyses on the topic, their prospective results were based on a population of unselected (consecutive) patients, including those with NYHA III/IV symptoms. In addition, unlike previous studies they have reported detailed data on drug dosages and ejection fraction. Therefore, they claimed that their results are more likely to be the representative of the clinical population of HFrEF patients with T2DM. They suggested that the underlying mechanism of their results may be linked to a higher sympathomimetic activity in T2DM.
Based on the above findings, the authors concluded that higher doses of bisoprolol may provide higher mortality benefits in HFrEF, and the subset of HFrEF patients with T2DM is particularly likely to derive higher mortality benefits from high-dose bisoprolol. The authors also emphasized that even among the HFrEF patients with T2DM, those with lower ejection fraction values can derive significant mortality benefits, regardless of the use of insulin therapy or the glycemic control. Therefore, based on these prospective data, the authors recommended a careful up-titration of bisoprolol in HFrEF patients with T2DM, which should be closer to the doses reached in clinical trials.
Reference
- Witte KK, Drozd M, Walker AMN, et al. Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes. Diabetes Care. 2018;41(1):136-142. doi:10.2337/dc17-1406
CODE: IN-BISOP-00001
