Intensive Glycemic Therapy in Patients With Type 2 Diabetes on β-Blockers

Glycemic control in patients with diabetes is necessary to prevent diabetes-related complications. Intensive glycemic control for patients with type 2 diabetes can decrease the risks for microvascular diseases, such as diabetic retinopathy and nephropathy (1), but the prevention of macrovascular diseases remains difficult. Recent large-scale randomized control trials (2–4) did not show the efficacy of intensive glycemic therapy for the prevention of cardiovascular events. In addition, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial revealed that intensive glycemic therapy can increase all-cause and cardiovascular mortalities (2). A possible explanation for these results is the fact that glucose-lowering therapy may increase the frequency of hypoglycemic episodes, which in turn is associated with increased risks for vascular events and mortality (5,6). In fact, patients with diabetes with severe hypoglycemia face many critical problems such as severe hypertension, hypokalemia, and QT prolongation, which could lead to cardiovascular disease, fatal arrhythmia, and death (7,8).

Recent studies have suggested that β-blockers may prevent or decrease the adverse influence of severe hypoglycemia, such as severe hypertension and hypokalemia, and may reduce severe hypoglycemia-associated cardiac arrhythmias and death (9,10). Therefore, the use of β-blockers may help to achieve maximum effects of glycemic control, particularly in intensive glycemic therapy, due to a decrease in the adverse influence of severe hypoglycemia. Although β-blockers theoretically pose a potential risk for the occurrence and prolongation of severe hypoglycemia (11), there is little evidence to support the assertion that β-blockers should be routinely contraindicated in patients with diabetes (12–18). In the current study, we assessed whether intensive glycemic therapy in patients with diabetes receiving treatment with β-blockers showed beneficial effects for the prevention of cardiovascular events without increased mortality, compared with a standard glycemic therapy.

We used ACCORD data to evaluate the associations between the use of β-blockers and cardiovascular events, and all-cause and cardiovascular mortalities in patients with type 2 diabetes. The detailed design and description of glycemia interventions of the ACCORD trial have been reported previously (2,19–21). Briefly, the ACCORD trial was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and was conducted in 77 clinical centers across the U.S. and Canada. In total, 10,251 men and women between 40 and 79 years of age with type 2 diabetes, a glycated hemoglobin level of ≥7.5%, and who either were between 40 and 79 years of age and had cardiovascular disease or were between 55 and 79 years of age and had albuminuria, anatomical evidence of significant atherosclerosis, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (current smoker, obesity, hypertension, or dyslipidemia) were included in the trial (2,19). Exclusion criteria included a BMI (weight in kilograms per square meters) of >45 kg/m², an unwillingness to perform home glucose monitoring or to inject insulin, frequent or recent serious hypoglycemia, a serum creatinine level of >1.5 mg/dL, or any other serious illness. All 10,251 patients were randomly allocated into one of the two groups: one group of patients received comprehensive intensive glycemic therapy that targeted a glycated hemoglobin level of <6.0%; and the other group of patients received standard glycemic therapy that targeted a level of 7.0–7.9%. The medications used to achieve these targets were the same in the two groups and included metformin, short-acting and long-acting insulins, sulfonylureas, acarbose, meglitinides, thiazolidinediones, and incretins. Patients were followed up at least every 4 months to ensure that therapeutic goals were met and maintained, and to monitor study outcomes and adverse effects. The study protocol was approved by the ethics committee of each study center, and approved and monitored by an independent data safety and monitoring board. All participants provided written informed consent. Because of the increase in all-cause and cardiovascular mortalities, intensive glycemic therapy was discontinued on 6 February 2008 (2). Participants were switched to the standard regimen and were followed up until 31 December 2010. The occurrence of outcomes in this study was maximally followed up for 7 years. This study was approved by the institutional review board of the National Center for Global Health and Medicine, and NHLBI has approved our use of the ACCORD data.

The primary outcome in this study was the first occurrence of a cardiovascular event, which included nonfatal myocardial infarction, unstable angina, nonfatal stroke, and cardiovascular death. Secondary outcomes were all-cause death, cardiovascular death, and severe hypoglycemia. Cardiovascular death was defined as presumed cardiovascular death; unexpected death; and death from a myocardial infarction, arrhythmia, congestive heart failure, stroke, and other cardiovascular diseases, including abdominal aortic aneurysm rupture and pulmonary emboli (19). Severe hypoglycemia was defined as hypoglycemic events with confirmed blood glucose levels of <50 mg/dL and requiring medical assistance.

Demographic data were presented as numbers with proportions (percentage) or means with SDs. Continuous variables were compared using Student t tests, and categorical variables were compared using χ² tests or Fisher exact tests, as appropriate. The study participants were first divided into two groups according to their use or nonuse of β-blockers. With the exception of severe hypoglycemia, the number of events occurring within 1 year was small, and there were concerns regarding subject identification. Therefore, before we analyzed the data, follow‐up times for all early events were trimmed to 1 year by the NHLBI. For cardiovascular events and all-cause and cardiovascular deaths within 1 year, we compared the incidences of these events by intensive glycemic therapy with standard glycemic therapy in each patient receiving treatment with and not receiving treatment with β-blockers. We analyzed hazard ratios (HRs) with 95% CIs in patients receiving intensive glycemic therapy compared with those receiving standard glycemic therapy by Cox proportional hazard models, again for each patient receiving treatment with and not receiving treatment with β-blockers. Analyses of events before the treatment transition were also performed. Kaplan-Meier survival curves were constructed for the cardiovascular events and all-cause and cardiovascular mortalities.

All statistical analyses were conducted using Stata software (version 14.1; StataCorp). P < 0.05 was considered statistically significant for all tests.

The characteristics of patients with type 2 diabetes receiving treatment with and not receiving treatment with β-blockers are presented in Table 1. Among the study patients, 3,079 were receiving treatment with β-blockers (standard glycemic therapy, n = 1,580; intensive glycemic therapy, n = 1,499) and 7,145 were not receiving treatment with β-blockers (standard glycemic therapy, n = 3,526; intensive glycemic therapy, n = 3,619). In patients receiving treatment with and not receiving treatment with β-blockers, the characteristics were not significantly different between those receiving standard glycemic therapy and those receiving intensive glycemic therapy. Characteristics, including age, sex, duration of diabetes, history of cardiovascular disease, smoking status, BMI, cholesterol and triglyceride levels, and estimated glomerular filtration rate, were significantly different between patients receiving treatment with and not receiving treatment with β-blockers. The rate of β-blocker use in patients with a history of coronary heart disease and heart failure was 66%, and that in patients without such a history was 21% (Supplementary Table 1), which indicated guideline-compliant β-blocker use for patients with a history of coronary heart disease and/or heart failure.

The incidences of cardiovascular events and all-cause and cardiovascular deaths within 1 year in all patients receiving intensive and standard glycemic therapies and in those receiving treatment with and not receiving treatment with β-blockers are presented in Fig. 1. In patients receiving treatment with and not receiving treatment with β-blockers, the incidences of cardiovascular events, all-cause death, and cardiovascular death were not significantly different between patients receiving standard and intensive glycemic therapies in the first year. Kaplan-Meier survival curves and the event rates for the following periods are shown in Fig. 2 and Table 2, respectively. The mean follow-up periods (±SD) were 4.6 ± 1.5 years in patients not receiving treatment with β-blockers and 4.3 ± 1.5 years in those receiving treatment with β-blockers. Consistent with previous studies on the ACCORD trials (2,21), the cumulative event rates for cardiovascular events were lower, and those for all-cause and cardiovascular deaths were higher, in the intensive therapy group compared with the standard therapy group (Fig. 2A, C, and E). In patients receiving treatment with β-blockers, the cumulative event rates for cardiovascular events were significantly lower in the intensive therapy group compared with the standard therapy group (HR 0.81; 95% CI 0.67–0.97; P = 0.02), whereas those in patients not receiving treatment with β-blockers were not significantly different (HR 0.92; 95% CI 0.78–1.09; P = 0.36) (Fig. 2B). Conversely, the cumulative event rates for all-cause and cardiovascular deaths in patients receiving treatment with β-blockers were not significantly different between the standard and intensive therapy groups (all-cause death: HR 1.08; 95% CI 0.83–1.42; P = 0.54; cardiovascular death: HR 1.05; 95% CI 0.72–1.51; P = 0.79), whereas in patients not receiving treatment with β-blockers, the event rates were significantly higher in the intensive therapy group compared with the standard therapy group (all-cause death: HR 1.25; 95% CI 1.02–1.52; P = 0.02; cardiovascular death: HR 1.43; 95% CI 1.03–1.98; P = 0.03) (Fig. 2D and F, respectively). In patients receiving treatment with and not receiving treatment with β-blockers, the cumulative event rates for nonfatal myocardial infarction and nonfatal stroke were nonsignificantly lower in the intensive therapy group compared with the standard therapy group (Table 2). The cumulative event rates for fatal or hospitalized congestive heart failure in patients receiving treatment with β-blockers were not significantly different between the standard and intensive therapy groups (HR 0.96; 95% CI 0.71–1.30; P = 0.80), whereas in patients not receiving treatment with β-blockers, the event rates were higher in the intensive therapy group compared with the standard therapy group (HR 1.23; 95% CI 0.92–1.64; P = 0.15).

Kaplan-Meier survival curves for cardiovascular events and all-cause and cardiovascular deaths in intensive and standard glycemic therapies before treatment transition in all patients and those receiving treatment with and not receiving treatment with β-blockers are shown in Fig. 3. Similarly, we found that the cardiovascular event rate in patients with diabetes receiving treatment with β-blockers was lower in the intensive therapy group than in the standard therapy group (HR 0.81; 95% CI 0.66–1.01; P = 0.06). In addition, the cumulative event rates for all-cause and cardiovascular deaths in patients receiving treatment with β-blockers were not significantly different between the standard and intensive therapy groups (all-cause death: HR 1.00; 95% CI 0.73–1.38; P = 0.96; cardiovascular death: HR 0.85; 95% CI 0.55–1.31; P = 0.48), whereas in patients not receiving treatment with β-blockers, the event rates were significantly higher in the intensive therapy group compared with the standard therapy group (all-cause death: HR 1.27; 95% CI 1.01–1.59; P = 0.03; cardiovascular death: HR 1.52; 95% CI 1.06–2.18; P = 0.02).

The HRs for severe hypoglycemia are presented in Supplementary Table 2. Although the event rates per year were higher in patients receiving treatment with β-blockers compared with those not receiving treatment with β-blockers, HRs for severe hypoglycemia in the intensive therapy group compared with the standard therapy group differed only slightly between those receiving treatment with β-blockers (HR 2.98; 95% CI 2.19–4.06; P < 0.001) and not receiving treatment with β-blockers (HR 2.87; 95% CI 2.27–3.62; P < 0.001). In the model that included the interaction term between the use of β-blockers and the type of therapy (intensive/standard glycemic therapy), we found that the association between intensive glycemic therapy and the incidence of severe hypoglycemia was not interacted by the use of β-blockers (P for interaction term = 0.86, data not shown).

In the current study, cardiovascular event rates in patients receiving treatment with β-blockers were significantly lower in the intensive therapy group compared with those in the standard therapy group. In addition, all-cause and cardiovascular mortalities in patients receiving treatment with β-blockers were not significantly different between the intensive and standard therapy groups. In contrast, in patients not receiving treatment with β-blockers, the cardiovascular event rate did not differ significantly between intensive and standard glycemic therapies, whereas all-cause and cardiovascular mortalities were significantly higher in the intensive therapy group.

A recent study on the ACCORD trial (21) reported that ischemic heart disease was less frequent in the intensive therapy group compared with the standard therapy group. Considering the results in the current study, the beneficial effects of intensive glycemic therapy might be due to the efficacy in patients receiving treatment with β-blockers. In addition, although a previous report on the ACCORD trial (2) demonstrated that intensive glycemic therapy was associated with an increased risk of all-cause and cardiovascular deaths, the current study found that the adverse effects of intensive glycemic therapy might be attributed to the effects of not receiving treatment with β-blockers. Some reports have indicated that severe hypoglycemia, of which intensive glycemic therapy was associated with higher risks, was associated with an increased risk of cardiovascular disease and death (5,6). One possible reason for the association between severe hypoglycemia and cardiovascular events is that severe hypoglycemia can lead to activation of the sympathoadrenal system and the release of counter-regulatory hormones, resulting in significant hemodynamic changes, hypokalemia, and QT prolongation (7,22). Based on pathophysiological mechanisms, a prior use of β-blockers may prevent the adverse influence of the hypersecretion of catecholamines induced by severe hypoglycemia, and that may reduce the number of vascular events, cardiac arrhythmias, and deaths due to severe hypoglycemia (7,10). Indeed, the analyses of patients receiving treatment with β-blockers showed that the cardiovascular event rate was significantly lower in the intensive therapy group compared with the standard therapy group. In addition, although data on arrhythmogenic cardiac mortality was not assessed, the number of all-cause and cardiovascular mortalities did not increase in the intensive therapy group in patients receiving treatment with β-blockers, which is different from the results of those not receiving treatment with β-blockers. The HRs for severe hypoglycemia in the intensive therapy group compared with the standard therapy group were not very different between patients receiving treatment with and not receiving treatment with β-blockers, and the association between intensive glycemic therapy and the incidence of severe hypoglycemia was not interacted by the use of β-blockers. Therefore, the decreased risk of cardiovascular events in patients receiving treatment with β-blockers might be due to the protective effects of β-blockers after the occurrence of severe hypoglycemia. Intensive glycemic therapy may be a preferable strategy to prevent cardiovascular events in patients receiving treatment with β-blockers, which were essential for treating underlying diseases, such as coronary heart disease and heart failure, compared with standard glycemic therapy. The beneficial effects of β-blockers on cardiovascular events may be observed in the high cardiovascular risk in patients with type 2 diabetes, partly because these patients may be at a higher risk of severe hypoglycemia and severe hypoglycemia-associated adverse events, and β-blockers may alleviate the damage from hypoglycemia-associated adverse events. It has been known that the use of β-blockers can be a risk factor for hypoglycemia and hypoglycemia unawareness, presumably because of diminished or absent early warning signs (11). However, there was little evidence to support the assertion that β-blockers should be routinely contraindicated in patients with diabetes as they have minimal clinical effects on hypoglycemia unawareness and recovery (12–16). Further studies are needed to evaluate whether the use of β-blockers in patients with diabetes shows beneficial or adverse effects.

This study has several limitations. First, this was a post hoc analysis of the ACCORD trial, and residual confounding might still be present. In addition, although the current study was large scale and evidence based, and had a robust subgroup representation, our findings may not be applicable to other patients with diabetes. Second, we were only able to analyze data that early events had been trimmed to 1 year. The number of events prior to 1 year was very small, and there were concerns regarding subject identification. Therefore, before we analyzed the data, follow-up times for all early events were trimmed to 1 year by the NHLBI. Although the incidences of cardiovascular events, all-cause death, and cardiovascular death in patients receiving treatment with and not receiving treatment with β-blockers were not significantly different between patients receiving standard and intensive glycemic therapies in a first year, another study is needed to confirm these results. However, we believe that the current study provides extremely important information regarding glycemic control and diabetes management. Third, adherence to medication, including β-blockers, might influence the study outcomes. Poor adherence to medication regimens is common and contributes to substantially worse cardiovascular outcomes (23). However, the average rate of adherence in clinical trials is usually high, owing to the monitoring programs and to the selection of the patients. Because follow-up visits in patients in the ACCORD trial, including a blood pressure trial, were conducted for at least 4 months, the rate of adherence to medications might be remarkably high. Fourth, we could not assess whether the different types of β-blockers, such as cardioselective and nonselective β-blockers, had similar effects on cardiovascular events and death. Although the β-blockers exert their effects by competitively inhibiting catecholamines from binding to β-receptors, each β-blocker has different characteristics with respect to the cardioselectivity, pharmacokinetics, intrinsic sympathomimetic activity, and α-adrenergic blocking activity. Thus, further studies are needed to clarify which types of β-blockers are more beneficial.

In conclusion, this study showed that the cardiovascular event rate in patients with diabetes receiving treatment with β-blockers was significantly lower in the intensive therapy group compared with the standard therapy group. In addition, all-cause and cardiovascular mortalities in those patients not receiving treatment with β-blockers were significantly higher in the intensive therapy group. Intensive glycemic therapy may be effective in patients with type 2 diabetes who are receiving treatment with β-blockers.

Acknowledgments. This article was prepared using ACCORD Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the ACCORD Study or the NHLBI.

Funding. This research was supported by Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (no. 26860701).

Duality of Interest. M.N. has received speaker honoraria from Sanofi, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Eli Lilly Japan, MSD, Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Astellas, Kowa Pharmaceutical Co. Ltd, Novo Nordisk Pharma Ltd, AstraZeneca, and Johnson & Johnson K.K. and research grants from Takeda Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma, and AstraZeneca. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. T.T. contributed to the study concept and design; data acquisition, analysis, and interpretation; and statistical analysis and drafted the manuscript. T.S. contributed to the data acquisition, analysis, and interpretation and statistical analysis and drafted the manuscript. M.N. and H.K. drafted the manuscript. T.T. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.