It's no secret that beta blockers are still greatly misunderstood, despite their long history of success. Less well-known, however, are the reasons why many health care providers hesitate to prescribe these medications to their patients with cardiovascular disease. It's the general opinion of the IMPACT Council that physician reluctance toward beta blockers may be due to a number of "myths" associated with their use. In an effort to help the medical community better understand the benefits of beta blockade, we have created a series of articles called, "Dispelling the Myths About Beta Blockers." Last week's inaugural issue challenged the assumption that all beta blockers are the same; this week, we examine the belief that beta blockers may not be safe and effective in patients with diabetes.
According to the National Diabetes Education Program, more than 18 million people in the US live with diabetes. Because these people also may have, or are at risk to develop, concomitant conditions, including hypertension (HTN), ischemic heart disease, cerebral neuropathy, and nephrotic disease, they may need to take additional medications. And although beta blockers have proven cardioprotective benefits, they are commonly thought to be contraindicated in the diabetic patient population, primarily because they may mask signs and symptoms of hypoglycemia by inhibiting insulin secretion and generating insulin resistance.
In addition, a six-year study conducted by researchers at Johns Hopkins School of Medicine suggested that using beta blockers to control HTN may actually increase a nondiabetic patient's risk for developing type 2 diabetes. During the study, researchers followed 12,550 non-diabetic adults aged 45-64 and discovered that people who took beta blockers to control HTN had a 28% higher risk of developing type 2 diabetes than did those who did not take medication. Incidentally, those who took other medications to treat HTN, such as diuretics, angiotensin-converting enzyme inhibitors (ACEIs), or calcium channel blockers, did not show an increased risk of developing diabetes.1
These conclusions could easily be enough to deter any physician from prescribing beta blockers for diabetics or nondiabetics. On the other hand, consider the conclusion reached by the authors of the Johns Hopkins study: Concerns about the risk of developing diabetes should not dissuade doctors from prescribing beta blockers for diabetic or nondiabetic adults who have HTN. In other words, they discovered that the benefits outweigh the risks, because beta blockers show reduction in morbidity and mortality in hypertensive diabetic patients.
Furthermore, an analysis of the literature regarding beta blockers does not provide data on adverse metabolic effects, higher risks of hypoglycemia, or fewer renoprotective effects, which might substantiate the hesitancy among physicians to prescribe beta blockers for diabetic patients. Quite the reverse – a lack of beta-blocker therapy for diabetic patients may actually increase cardiovascular (CV) mortality. For example, a study by Haffner et al compared the incidence of fatal and nonfatal myocardial infarction (MI) in 1373 nondiabetic subjects and in 1059 diabetic subjects. The seven-year incidence rates of MI in nondiabetic subjects with and without prior MI at baseline were 18.8% and 3.5%, respectively (P<0.001), and the seven-year incidence rates of MI in diabetic subjects with and without prior MI at baseline were 45.0% and 20.2%, respectively (>P<0.001). The authors concluded that diabetic patients without previous MI have as high a risk of MI as nondiabetic patients with previous MI, and therefore, it is prudent to treat CV risk factors in diabetic patients as aggressively as they would be treated in nondiabetic patients with prior MI.2
In addition, a retrospective study of elderly diabetic patients demonstrated that beta-blocker treatment resulted in a lower one-year mortality rate than nontreatment. After MI, beta blockers have twice the protective effect in diabetic patients than in nondiabetic patients, mortality was similar to that of nondiabetic patients, and there was no increase in hospital admissions due to diabetic complications.3 And the results of UKPDS 39, a study of type 2 diabetes with treatment goals of tight control or less tight control of blood pressure (BP), showed a reduction in diabetes-related deaths, a reduction in the incidence of heart failure (HF) and stroke, and a significant reduction in the incidence of microvascular disease among patients assigned to tight BP control using an ACEI or a beta blocker. Importantly, the study showed that beta blockers worked as well as ACEIs to prevent the endpoints of renal failure, vitreous hemorrhage, or photocoagulation.4
Despite the findings of clinical trials, the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) had at one time advised against the use of beta blockers in diabetic patients due to concerns about the risk of prolonged hypoglycemia, masking of hypoglycemia, and diminished peripheral blood flow associated with beta blockers. Interestingly, later studies showed that the concern surrounding beta blockers' ability to obscure the warning symptoms of hypoglycemia seemed to be a problem in a minority of patients with type 1 diabetes, and was not seen in the majority of patients with type 2 diabetes patients.5 Furthermore, sweating, which is the primary symptom of hypoglycemia, was actually enhanced by both nonselective and selective beta blockers.6 Nonselective beta blockers may delay the physiologic correction of hypoglycemia during an acute episode because glucagons and adrenaline mediate glycogenolysis and glucose production via beta-2 receptors in the liver and in muscle.
However, in controlled metabolic studies, selective beta blockers such as ER metoprolol succinate and atenolol did not prolong hypoglycemia or interfere with glucagon and adrenaline-mediated recovery.5 Nonselective beta blockers can affect glucose tolerance in diabetic patients, and hyperosmolar coma has been reported as a complication with the use of propranolol. In contrast, selective beta blockers have not been shown to cause significant deterioration in glycemic control.6 As a result of these findings, JNC has since revised its recommendations to include beta blockade as beneficial therapy to reduce the incidence of CV disease and stroke in diabetic patients.7
Ultimately, beta blockers save lives and provide significant CV benefits, despite their side effects. Diabetic patients can take beta blockers to control or prevent CV complications related to diabetes, provided they are titrated slowly, and glycemic control and lipid levels are monitored. Before prescribing beta blockers to them, physicians should determine if nondiabetic patients have a family history of type 2 diabetes or belong to ethnic groups that are at high risk for diabetes (African Americans, Hispanics, Native Americans).
One of the most common myths about beta blockers, and one we dispelled earlier in the series, is that they should not be given to patients with diabetes. This misconception stems largely from the belief that beta blockers are contraindicated in high-risk patients such as diabetics because the drug may mask symptoms of hypoglycemia. However, very little data support the notion that using beta blockers results in significant adverse metabolic effects, higher risks of hypoglycemia, or a lessening of renoprotective effects.
In fact, in many situations, treating diabetic patients with beta blockers significantly decreases cardiovascular events without increasing the adverse event rate. For example, in the UKPDS trial (UKPDS 39), which studied type 2 diabetes with treatment goals of tight control or less tight control of blood pressure (BP), using an angiotensin-converting enzyme inhibitor (ACEI) or a beta blocker, showed equivalent reductions in diabetes-related deaths, the incidence of heart failure (HF), and stroke.1
But what about HF patients with diabetes — can they experience similar benefits with beta blockade? Two studies, the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) and the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) trial, had sufficient numbers of diabetic patients to answer this question. In both, patients with diabetes achieved similar reductions in events to nondiabetic subjects.
For COPERNICUS, the effects of carvedilol and placebo were examined in 589 diabetic patients and in 1700 nondiabetic patients.2 Both groups had HF symptoms at rest or on minimal exertion. During the 10-plus months of follow-up, carvedilol was both well tolerated and produced favorable effects on all outcome variables that were similar in both diabetics and nondiabetics. Neither group experienced an excess risk of hyperglycemia or renal dysfunction. Diabetics treated with carvedilol were somewhat more likely to report hypoglycemia, yet less likely to experience presyncope than nondiabetics; however, the incidence of both events was low.
The MERIT-HF study evaluated the efficacy and safety of metoprolol CR/XL (now referred to as ER metoprolol succinate) in a sub-group of 985 diabetic patients.3 Mean left ventricular ejection fraction was 28%, while 62% of patients had New York Heart Association (NYHA) class II HF and 34% of patients had NYHA class III HF. During the 12-month follow-up, diabetic patients on metoprolol CR/XL experienced significantly lower rates of all-cause mortality and HF hospitalization compared to placebo. The discontinuation rate due to an adverse event or worsening HF was significantly less in patients taking metoprolol CR/XL than placebo.
Findings from these two landmark studies demonstrate that in diabetic patients, beta-blocker therapy is well-tolerated and significantly reduces mortality and hospitalization rates for HF. In addition, the seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) classified diabetes as a "compelling indication" for antihypertensive combination therapy that includes beta blockers - a therapy regimen that can prevent or slow the progression to HF.4
In other words, says IMPACT Faculty Member Michael J. Bloch, MD, don't let mythology keep you from treating needy patients with beta blockers.
"All the available data suggest that we do a great disservice to our diabetic patients with HF when we withhold beta-blocker therapy due to unfounded concerns about adverse effects in this high-risk population," he states.
IMPACT Faculty Member Michael J. Bloch, MD, is Assistant Professor in the Division of General Internal Medicine, Department of Internal Medicine at the University of Nevada. He is also Medical Director of an innovative community cardiovascular Risk Reduction Center at Saint Mary's Heart and Vascular Institute in Reno, NV.