Beta-blockers in Type 2 Diabetes: Time to Reconsider?

Beta-blocker use in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) risk factors is associated with an increased risk of CV events and severe hypoglycemia, according to a recent study.

“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,”¹ wrote lead author Hiroshi Kajio, MD, PhD, of the National Center for Global Health and Medicine, Tokyo, Japan, and colleagues.

While appropriate glycemic control can decrease the risk of diabetic complications, going too far may be counterproductive. Results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial suggest that intensive glucose-lowering therapy is associated with increased hypoglycemia and mortality, which led to discontinuation of the trial after 3.5 years.² One explanation for these results is that intensive glucose lowering can increase hypoglycemic episodes, which in turn are associated with a heightened risk of vascular events and death.

During episodes of severe hypoglycemia, β-blockers may serve a protective function by decreasing hypoglycemia-related cardiac arrhythmias, severe hypertension, and CV events. However, β-blockers themselves can increase the risk of severe hypoglycemia. They may also dampen early warning signs and contribute to hypoglycemia unawareness. β-blockers also may lead to weight gain, which may increase the risk of CV events over time.

This raises the question: How effective are β-blockers in patients with T2DM? To find an answer, researchers performed a post-hoc analysis of data from the ACCORD trial. The study took place in 77 clinical centers in the US and Canada and included 10,251 people with T2DM, inadequately controlled hemoglobin A1c, and preexisting CV disease (or at increased risk for it).

Participants were randomized to intensive glucose-lowering therapy or standard therapy. The mean follow-up time was slightly over 4.5 years.

Results/Conclusion/Take-home message>

RESULTS

► Overall, significantly higher risk of CV events and CV death associated with beta blockers:

   ► CV events: 46% increased risk (HR, 1.46; P < .001)

   ► CV death: 44% increased risk (HR, 1.44; P = .02)

   ► All-cause death slightly increased, but results not significant

► Presence of coronary heart disease (CHD)/heart failure (HF): risk of CV events significantly increased by 27% (HR, 1.27; P = .03)

► No CHD/HF: risk of CV events significantly increased by 45% (HR, 1.45; P = .002)

► Intensive therapy: risk of CV events increased by 4%, but results not significant (HR, 1.04; P = .75)

► Standard therapy: risk of CV events significantly increased by 69% (HR, 1.69; P < .001)

► Severe hypoglycemia: significantly increased risk by 36% (HR, 1.36; P = .01)

The authors explained that the elevated risk of CV events associated with β-blockers was at least partly related to increased severe hypoglycemia, and that this risk may outweigh the protective effect β-blockers may have during severe hypoglycemia. However, they also noted that some subgroups may not have been large enough to reach statistical significance for variables such as CV death and all-cause death. “Newly randomized controlled trials are required to evaluate whether the use of β-blockers in patients with diabetes mellitus shows beneficial or adverse effects,” they concluded.

Take-home points

♦ Post-hoc analysis of the ACCORD trial data suggests that the risk of CV events and severe hypoglycemia is higher in patients with T2DM and established CV risk factors who take β-blockers, compared with those who do not.

♦ β-blockers are associated with a significantly increased risk of CV events in patients with or without CHD/HF and those receiving standard therapy.

♦ Increased risk of CV events associated with β-blockers may outweigh their protective effect on the heart and vasculature during hypoglycemia.

♦ The indication for β-blockers in T2DM may need reconsideration, but randomized controlled trials are needed.

References:

1. Tsujimoto T, Sugiyama T, Shapiro MF, et al. Risk of cardiovascular events in patients with diabetes mellitus on β-blockers. Hypertension. 2017;70:103-110.

2. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.