Protecting the heart and helping to reduce mortality, a closer look at beta-adrenoceptor inhibition in diabetes.
Chronic heart failure (CHF) with reduced left ventricular ejection fraction (LVEF) affects millions. Recent studies have shown that it ranks second as a cardiovascular complication of type 2 diabetes. A prospective cohort study showed the significant prognostic disadvantages had by patients with diabetes and CHF with left ventricular systolic dysfunction (LVSD). These patients had an increased risk of death threefold in comparison to the control group. In the last 30 years, treatment options have evolved, significantly reducing the mortality rate of patients with CHF. These treatment options include two select disease-modifying drug classes: ACE-inhibitors and beta-blockers, making them the pillars of CHF treatment. Studies have examined the safety and efficacy of beta-blockers use in patients with diabetes and reduced left ventricular ejection fraction, but there have not been studies conducted to compare the two cornerstone agents for CHF in patients with and without diabetes. Klaus K. Witte, et al. took the opportunity to do just that.
A prospective cohort study was conducted in the UK to determine whether beta blockers and ACE inhibitors (ACEIs) are connected to dose-related effects on mortality in patients who have CHF with and without diabetes. The authors hypothesized that higher doses would be associated with a greater reduction in mortality for patients who have CHF with or without diabetes. 1,797 patients were included in this study if stable signs and symptoms of CHF were present for at least 3 months, they were 18 years of age or older, had an LVEF of £45%, and provided medical history with written consent. Diabetes status and symptomatic status according to New York Heart Association Functional Classification (NYHA) were documented. Data that was analyzed included patient’s venous blood, estimated glomerular filtration rate (eGFR), two-dimensional echocardiogram images, and the measured resting heart rate via 12-lead electrocardiograms. Prescribed doses of medications were analyzed against comparative drugs in each class (mg/day). More specifically, patient’s select ACE inhibitor was compared to an equivalent dose of ramipril and beta-blocker to bisoprolol. Loop diuretics were included, but weren’t significant to this study. Student t tests or ANOVA was used to measure continuous data and a two-sided Pearson c2 test was used to measure categorical data.
Results showed that 28% of the studied patients had diabetes with a mean HbA1c of 7.8%. The majority of these patients (38.8%) used metformin for glycemic control. The patients who had diabetes were more likely to have lower hemoglobin, lower eGFR, belong to NYHA class III/IV, have less impaired left ventricular function and be prescribed higher doses of loop diuretics. Higher doses of beta-blockers and ACEIs were also given to this group although their heart rates were similar to those without diabetes. In this study, 84.8% of patients were prescribed a beta-blocker, with bisoprolol being the predominant choice. Low dose was considered <2.5mg/day of bisoprolol or ramipril equivalent, medium dose was 2.5-7.4mg/day, and high dose was ³7.5mg/day. The analyses of diabetes and the relationship between beta-blocker doses or ACEI doses and mortality showed that higher doses were associated with lower-all cause mortality in all patients without diabetes stratified. This made a greater impact on the population with diabetes when days of survival lost per patient during the first 5 years was calculated. Patients without diabetes and no beta blocker or ACEI lost 448 days (95% CI 347-549) and 478 days (95% CI 344-611) respectively, while only 326 days (239-413) and 287 days (220-355) were lost while on high dose bisoprolol or ramipril therapy respectively. Patients with diabetes and no beta blocker or ACEI lost 712 days (527-896) and 774 days (95% CI 534-1,013) respectively, while only 355 days (227-482) and 391 days (282-499) were lost while on high dose bisoprolol or ramipril therapy respectively. The Cox regression analysis showed that for every milligram/day increment of bisoprolol dose, patients without diabetes showed a 3.5% (0.7-6.3) reduction in mortality, while those with diabetes had an 8.9% (5-12.6) reduction in mortality (p-value= 0.027), showing significant. Ramipril’s mg/day increments showed less significance when analyzed through the Cox regression model: patients without diabetes showed a 5.1% (2.6-7.6; p=0.76) reduction in mortality vs. the 5.9% (2.5-9.2; p=0.76) reduction in patients with diabetes. After a mean follow-up of 4 years, it was found that 494 patients without diabetes and 241 patients with diabetes died.
In conclusion, this study provides important treatment information for patients with diabetes and CHF. The most important findings are higher doses of beta blockers and ACEI are associated with lower mortality in patients with CHF and LVSD. Patients with diabetes and CHF may benefit more from high dose beta-blocker therapy. The association is more pronounced in these patients. Also, it is important to note that beta blocker dose and mortality was not associated with glycemic control or insulin therapy. Some limitations of this study include generalizability, patients with CHF were not included in the study and preserved ejection fraction. More limitations include: mode of death was not studied, no data on hypoglycemic episodes, and causality in the associations cannot be inferred.
- ACEI and Beta-blockers are the mainstay in CHF treatment.
- High doses of beta blockers and ACEI are associated with lower mortality in patients with CHF and LVSD.
- Patients with diabetes and CHF may have a great benefit from higher doses of beta blockers.
Witte, Klaus K., et al. “Mortality Reduction Associated With b2-Adrenoceptor Inhibition in Chronic Heart Failure is Greater in Patients With Diabetes.” Diabetes Care, vol. 41, no. 1, 1 Jan. 2018, pp. 136-142., doi:10.2337/dc17-1406.
Adrianna Jackson, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy