Analyses from ACCORD trial show that β-blockade increases cardiovascular events, deaths, all-cause mortality and severe hypoglycemia in adults with diabetes. Similar trends were seen in patients with established coronary heart disease and heart failure.

A possible mechanism is the reduced sympathetic tone from β-blockade, which in turn lowers the body’s ability to sense and negate hypoglycemia. Evidence is mounting that prolonged hypoglycemia can lead to arrhythmias and cardiovascular events. 

Findings imply that strong indications are needed to prescribe b-blockers in patients with diabetes.

GT

Hypertension

ACCORD Trial

May 2017

Although the use of β-blockers may help in achieving maximum effects of intensive glycemic control due to decrease in the adverse effects after severe hypoglycemia; they pose a potential risk for the occurrence of severe hypoglycemia.

This study aimed to evaluate whether the use of β-blockers is effective in patients with diabetes mellitus, and whether its use is associated with the occurrence of severe hypoglycemia. Using the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) data, we performed Cox proportional hazards analyses with a propensity score adjustment.

The primary outcome was the first occurrence of a cardiovascular event during the study period, which included nonfatal myocardial infarction, unstable angina, nonfatal stroke, and cardiovascular death. The mean follow-up period was 4.6 years in patients on β-blockers (n=2527) and 4.7 years in those not on β-blockers (n=2527).

Results:

The cardiovascular event rate was significantly higher in patients on β-blockers than in those not on β-blockers (hazard ratio, 1.46; P<0.001).

In patients with coronary heart disease or heart failure, the cumulative event rate for cardiovascular events was also significantly higher in those on β-blockers than in those not on β-blockers (hazard ratio, 1.27; P=0.03).

The incidence of severe hypoglycemia was significantly higher in patients on β-blockers than in those not on β-blockers (hazard ratio, 1.30; P=0.02).

Conclusion:

The use of β-blockers in patients with diabetes mellitus was associated with an increased risk for cardiovascular events [and severe hypoglycemia]

More from the publication:

Diabetes mellitus management mainly aims at preventing diabetes mellitus–related complications. Although appropriate glycemic control prevents complications, the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) revealed that intensive therapy can increase all-cause and cardiovascular mortalities. A possible explanation for the results is that a glucose-lowering therapy increases the frequency of hypoglycemic episodes, which in turn is associated with increased risks for vascular events and death. Patients with diabetes mellitus with severe hypoglycemia face many critical problems, such as severe hypertension, hypokalemia, and QT prolongation, resulting in cardiovascular diseases, fatal arrhythmia, and death.

Recent studies have suggested that β-blockers may prevent or decrease the adverse effects after the occurrence of severe hypoglycemia, such as severe hypertension and hypokalemia, and may reduce severe hypoglycemia-associated cardiac arrhythmias and death. 

This does not necessarily mean that the use of β-blockers is effective in patients with diabetes mellitus because the use of β-blockers poses a potential risk for the occurrence of severe hypoglycemia. Therefore, we evaluated whether the use of β-blockers was effective in patients with diabetes mellitus and whether its use was associated with the occurrence of severe hypoglycemia in recent diabetes mellitus management.

In the present study using the ACCORD trial data, various analyses in propensity score-matched patients revealed that the use of β-blockers was associated with an increased risk for cardiovascular events. Furthermore, a similar relationship between the use of β-blockers and cardiovascular events was found in patients not only without heart disease but also with heart disease. The incidence of severe hypoglycemia was significantly higher in those on β-blockers than in those not on β-blockers.

Although an increased risk for hypoglycemia in patients with diabetes mellitus on β-blockers was hard to demonstrate, it has been well known that the use of β-blockers can be a risk factor for severe hypoglycemia and hypoglycemia unawareness presumably because of the diminished or absent early warning signs. Previous studies have suggested that the sympathoadrenal activation response to severe hypoglycemia is associated with cardiovascular events.

This study demonstrated that the use of β-blockers was associated with an increased risk for cardiovascular events, partly because of an increased occurrence of severe hypoglycemia. This risk may outweigh the benefit of decreasing adverse effects after the occurrence of severe hypoglycemia. However, several subgroup analyses could reveal the presence of other risks of β-blocker use. In particular, in the standard therapy group, the incidence of severe hypoglycemia was not significantly different between patients on and those not on β-blockers, whereas the incidence of cardiovascular events was significantly higher in patients on β-blockers than in those not on β-blockers. Therefore, the association between β-blocker use and the increased risk for cardiovascular events might not be explained only by an increase of severe hypoglycemia. Although the exact reason remains unclear, possible explanations include increased risks for nonsevere hypoglycemia, prolonged hypoglycemia, and weight gain because of β-blocker use, which can lead to increased risks of cardiovascular events. Further studies are needed to reveal the detailed mechanisms explaining the association between β-blocker use and the increased risk for cardiovascular events.

The present study revealed that the use of β-blockers in diabetes mellitus patients not only without heart disease but also with heart disease was associated with an increased risk for cardiovascular events. Many studies have demonstrated that β-blockers improve symptoms, reduce the risk of hospitalization, and prolong survival in patients with heart failure with reduced ejection fraction. In addition, β-blockers are recommended in many guidelines as the first-line therapy in patients with stable ischemic heart diseases. However, β-blockers have never been demonstrated to decrease mortality in patients without myocardial infarction or in those without heart failure associated with a reduction in the left ventricular systolic function. A recent study on diabetes mellitus patients with coronary heart disease suggested that the use of β-blockers was not effective in reducing all-cause mortality and cardiovascular events in those without myocardial infarction or heart failure with reduced ejection fraction. Several disadvantages of β-blockers may be equal to the benefits in diabetes mellitus patients with coronary heart disease.

This study has several limitations. First, although this study was large-scale, evidence-based, and with a robust subgroup representation, this was a post hoc analysis of the ACCORD trial. Patients in this study had glycated hemoglobin levels ≥7.5% and any cardiovascular risks. Therefore, our findings may not be applicable to other diabetes mellitus patients. Second, because the number of events prior to 1 year was low enough that there were concerns regarding subject identification, we could only analyze data where early events had been trimmed to 1 year. However, our analyses revealed that the use of β-blockers was associated with an increased risk of cardiovascular events; using continuous follow-up data, we assumed that all events trimmed to 1 year occurred at 6 months. Third, using an alpha error of 5%, the powers for the analyses were calculated to be 70.5% for cardiovascular events, 8.1% for all-cause death, and 23.0% for cardiovascular death. The present study might not have sufficient subjects to avoid beta errors. Therefore, to verify our findings, more large-scale studies are needed. Fourth, this study used the propensity score to minimize the effects of the many confounders, which could be related to the indication of β-blockers. Additional adjustment with patient health status further minimized the confounding by indication. However, residual confounding such as follow-up periods and unknown variables could influence the results. The propensity score-matched analysis might not have fully alleviated these differences in the risk for cardiovascular events. Therefore, newly randomized controlled trials are required to evaluate whether the use of β-blockers in patients with diabetes mellitus shows beneficial or adverse effects.

Using the ACCORD trial data, this study demonstrated that the use of β-blockers was associated with an increased risk for cardiovascular events and severe hypoglycemia in the modern era. Furthermore, a similar relationship between the use of β-blockers and cardiovascular events was found in patients with heart disease.

The indication of β-blockers may need to be reconsidered when this connection is elucidated through future higher-level evidence.