Use of beta-blockers may be associated with an increased mortality risk in patients with diabetes, particularly among those who have coronary heart disease (CHD), new research suggests.

The findings, from prospective cohort data from the US National Health and Nutrition Examination Survey 1999–2010, were published in the April issue of Mayo Clinic Proceedings by Tetsuro Tsujimoto, MD, PhD, of the Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, Tokyo, Japan, and colleagues.

Among nearly 3000 participants with diabetes, all-cause mortality over 5 to 6 years was significantly higher in those taking beta-blockers than those who were not, with an even more pronounced effect among those with CHD.

In contrast, among nearly 15,000 participants without diabetes who had CHD, all-cause mortality was significantly reduced among those who took beta-blockers versus those who didn't.

Beta-adrenergic receptor blockers have been shown to improve survival in patients following myocardial infarction (MI), and in those with congestive heart failure (CHF) because of left ventricular systolic dysfunction.

But beyond that, Tsujimoto and colleagues note, "Beta-blockers have never been found to improve survival in all other patients with stable CHD in the absence of [MI] or CHF without systolic dysfunction. Moreover, the efficacy of beta-blockers in diabetic patients with CHD/CHF remains unknown."

The new findings for people with diabetes are "sobering," say Franz H Messerli, MD, and Thomas Suter, MD, of the Department of Cardiology and Clinical Research, University Hospital Bern, Switzerland, and Sripal Bangalore, MD, Leon H Charney Division of Cardiology New York University School of Medicine, in an accompanying editorial.

"Unfortunately, under the umbrella of cardioprotection...solid evidence gathered in these post-MI trials has been uncritically extrapolated to other indications, such as hypertension, diabetes, chronic kidney disease, and even cerebrovascular disease. Despite the lack of evidence, the marketing of beta-blockers for such comprehensive cardioprotection proved to be exceedingly successful, and many of these ill-documented beta-blocker indications have persisted in the minds of physicians up to today," Messerli and colleagues write.

What's more, both the study authors and the editorialists point out that much of the data in support of beta-blocker benefit come from studies carried out decades ago, prior to the era of reperfusion and current pharmacologic therapies such as new oral anticoagulants, lipid-lowering agents, and renin-angiotensin system blockers.

"If nothing else, these powerful drugs have significantly reduced the overall risk in post-MI patients and, as a consequence, made it more difficult to document the possible benefits of beta-blockers," the editorialists say.

And in people with diabetes in particular, increased hypoglycemia and weight associated with beta-blockers may contribute to adverse outcomes, along with the possibility that the agents increase central blood pressure, which would be expected to be more pronounced in people with stiffer arteries, as is the case for many with diabetes.

Differing Effects Seen by Diabetes, CHD Status

The study population was comprised of 2840 participants with diabetes, of whom 697 were taking beta-blockers, and 14,684 without diabetes, including 1584 who were taking beta-blockers. Both CHD and CHF were more prevalent in those taking, versus not taking, beta-blockers (P < .001).

Among those with diabetes, all-cause death event rates per 1000 person-years were 40.6 for those taking beta-blockers versus 17.1 for those not taking them. Among participants without diabetes, those rates were 13.8 and 5.9, respectively.

In multivariate analysis, the adjusted hazard ratio (HR) for all-cause mortality among those with diabetes for those taking, versus not taking, beta-blockers was 1.49 (P = .01).

Similar results were found for those taking β 1 -selective beta-blockers (adjusted HR, 1.60; P = .007) and those taking specific beta-blockers (bisoprolol, metoprolol, and carvedilol) compared with those not taking beta-blockers (adjusted HR, 1.55; P = .01).

Among participants without diabetes, the adjusted HR didn't differ significantly between those taking and not taking beta-blockers (0.99; P = .96).

In addition, all-cause mortality was significantly higher among those with diabetes and CHD who were taking beta-blockers versus those who weren't (adjusted HR, 1.64; P = .02), whereas the risk was significantly lower with beta-blockers among those who had CHD but didn't have diabetes (adjusted HR, 0.68; P = .02).

A propensity score-matched Cox proportional hazards model yielded similar results.

Tsujimoto and colleagues conclude, "Use of beta-blockers may be associated with an increased risk of mortality for patients with diabetes and among the subset who have CHD. Further studies are needed to assess whether beta-blockers are effective in reducing mortality and coronary events in diabetic patients receiving optimal medical treatment."

Messerli and colleagues commented, "We wholeheartedly agree."

The study was supported by grants from the Japan Society for the Promotion of Science (KAKENHI) and National Center for Global Health and Medicine. Messerli is a consultant for or has advisory relationships with Daiichi-Sankyo, Pfizer, Abbott, Servier, Medtronic, WebMD, Menarini, and Ipca. Bangalore is a consultant for or has advisory relationships with Daiichi-Sankyo, Pfizer, Abbott, Amgen, Menarini, Abbott Vascular, Merck, AstraZeneca, and The Medicines Company.

Mayo Clin Proc. 2018;93:409-418. Abstract, Editorial

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.