In this issue...

• Diabetes: Direct correlation with CAD
• Clearing the myths
  
• UKPDS: The Beta-Blocker "Surprise" for hypertensive diabetics
  
• Cardioprotective role of beta-blockers in diabetic survivors of MI: Collective evidence
  
• Inference from evidence
• Optimizing current beta-blocker therapy: The introduction of extended-release metoprolol

Beta-blockers have an established role in cardioprotection both in primary and secondary prevention studies. There is enormous evidence that beta-blockers (especially lipophilic) reduce coronary mortality. Furthermore, there is good evidence from recent studies that diabetics, elderly and those with impaired left ventricular function do derive considerable benefit from beta-blockade. Yet, studies indicate that beta-blockers are vastly underutilised.

'b Scope', in the current and subsequent issues, attempts to provide the current evidence-based perspective on the use of beta-blockers in special patient populations. This inaugural issue describes and evaluates the common reasons for withholding beta-blockers from diabetic patients and provides treatment recommendation based on evidence.

Diabetes:
Direct correlation with CAD

Today, India leads the world with its largest number of diabetic subjects in any given country. It has been estimated that presently 19.4 million individuals are affected by diabetes and these numbers are expected to increase to 57.2 million by the year 2025 (one-sixth of the world total).1 Hypertension and diabetes coexist more frequently than would be expected from the prevalence of each in the general population. Hypertension is seen in 30-58% of patients with non-insulin dependent diabetes mellitus (NIDDM).2

Coronary artery disease (CAD) mortality and the incidence of non-fatal CAD events are two to four times higher in type 2 diabetic patients compared to age-matched non-diabetic subjects. In the CUPS (Chennai Urban Population Study) study, it was shown that 21.4% of the diabetic population had CAD. Also, it was noted that at every age point, diabetic subjects had a higher prevalence of CAD compared to their non-diabetic counterparts.1

Figure 1. Survival of patients with and without diabetes from admission of 1-year following acute myocardial infarction (P<0.001).

 

Clearing the myths

a. Hypoglycemic unawareness and delayed recovery:
The first concern for prescribing beta-blockers is that these drugs obscure the warning symptoms of hypoglycemia, a complication of diabetes treatment. Symptoms such as palpitations, tremor and anxiety are mediated by sympathetic outflows of adrenaline that stimulate beta-receptors and serve to warn patients of hypoglycemia.

However studies have shown that even if some symptoms are blunted by beta-blockade, hypoglycemic unawareness to a dangerous extent is only a problem in a minority of Type 1 diabetes patients, and is not encountered in the vast majority of type 2 diabetes patients.3

Studies have shown that in diabetic as well as non-diabetic patients there is no increased risk of serious hypoglycemia or that of hospitalization for hypoglycemia with the use of nonselective or selective beta-blockers.2,3 Indeed in one study2, adrenaline release was triggered off at a significant higher plasma glucose level, and the threshold for growth hormone, cortisol and glucagon release was unchanged. Moreover, the peak responses of adrenaline and growth hormone were significantly higher for metoprolol than placebo.

Furthermore, sweating, the prime symptom of hypoglycemia was actually enhanced by both non-selective and selective beta-blockers.2

Non-selective beta-blockade during an acute episode of hypoglycemia may delay the physiological correction of hypoglycemia. This is because glucagons and adrenaline mediate glycogenolysis and glucose production via b2 receptors in liver and muscle. However, in controlled metabolic studies, cardioselective beta-blockers (metoprolol and atenolol) have been reported to neither prolong hypoglycemia nor interfere with glucagon and adrenaline- mediated recovery.3

Non-selective beta-blockers have been shown to affect glucose tolerance in diabetic patients and hyperosmolar coma has been reported as a complication of the use of propranolol. In contrast, the use of cardioselective beta-blockers has not been shown to lead to a significant deterioration in glycemic control.2

As the beneficial effects of beta-blockers are mediated through blockade of b1 receptors and the negative impact on glycemic control is mediated by the b2 receptors, only b1 selective blockers should be prescribed in diabetic patients.

Hence selective beta-blockers appear to be safe and fears of reduced hypoglycemic awareness and recovery are unsubstantiated.2

b. Increased insulin resistance:
Increased insulin resistance and the possibility of hyperglycemia are also frequently cited, but insufficient grounds for withholding beta-blocker therapy in diabetic patients. It is assumed that the addition of a beta-blocker will exacerbate insulin resistance and lead to compromised blood sugar control. These effects may be, however, lesser with use of cardioselective beta-blockers.

Good glycemic control is achievable in beta-blocker users through a regimen of weight loss, exercise, diet, oral hypoglycemic agents and insulin; small perturbations of blood sugar can, and should be treated by manipulating these factors.3

Although insulin resistance and hyperglycemia are potential adverse events attributable to beta-blockers, there is little evidence that this is an important clinical problem. In a prospective cohort of 2,723 patients with diabetes and established coronary artery disease, patients on beta-blockers (n = 911) had lower fasting blood glucose, the same use of hypoglycemic therapies, and lower mortality than patients not using beta-blockers.3

c. Dyslipidemia:
By interfering with hepatic lipoprotein synthesis and peripheral lipoprotein lipase activity, beta-blockers have consistently been shown to induce a state of dyslipidemia. This is characterized by an elevation of triglycerides, a decrease in high density-lipoprotein levels, and no change in low-density lipoprotein or total cholesterol levels. However it seems that non-selective drugs have a more consistent effect on HDL and this may be due to effects on lipoprotein lipase responsible for the removal of endogenous triglycerides.3 Non-selective beta-blockade exposes uninhibited alpha stimulation, which inhibits the lipase responsible for degrading triglycerides; whereas b1 selective agents permit b2 stimulation to counteract these effects.

Blood lipid changes with highly b1 selective agents, are minimal or absent. Further, the clinical significance of b2 blockade-induced lipid changes is unclear,
particularly as non-selective agents like propranolol and timolol have been shown to be highly effective in reducing post infarction mortality and reinfarction.2 Beta-blockers have also consistently been shown to prevent reinfarction and death after acute myocardial infarction, a benefit that is essentially undiminished in the presence of adverse changes in serum lipids.3 However, beta1 blockade appears to be the active ingredient in cardiovascular protection and it therefore seems logical to choose a highly beta1 selective agent.2,4

Protective properties of beta-blockers

Beta-blockers possess properties beyond their ability to lower blood pressure4: Anti-ischaemic, anti-arrhythmic, anti-atherosclerotic and anti- renin/angiotensin properties, Prolongation of coronary diastolic filling time, Upregulation of cardiac b1 receptors and inhibition of stimulatory anti b1-receptor autoantibodies, Augmentation of atrial and brain natriuretic peptide, Reduction of plasma endothelin-1 levels (carvedilol), Stimulation of endothelial L-arginine/nitric oxide pathway (vasodilatory beta-blockers such as nebivolol) and Inhibition of catecholamine-induced cardiac necrosis (apoptosis)

Importantly, patients with diabetes mellitus are at high risk of developing coronary artery disease and of dying from the consequences. Many die suddenly. b-blockers are the group of drugs for which there is maximum evidence for reducing the risk of dying from coronary artery disease and they are particularly effective in reducing the risk of sudden death.5

The evidence on the beneficial effects of beta-blockers in primary and secondary prevention with respect to their lipid solubility is summarized in Table 1.

UKPDS:
The Beta-Blocker "Surprise" for hypertensive diabetics

The publications of the classic UK Prospective Diabetes Study Group (UKPDS)4 have changed the overall viewpoint about beta-blockers and the treatment of type II diabetics with hypertension.

In the UKPDS study, type II diabetes patients with hypertension (n=1148) were randomized to either tight control of blood pressure (BP < 150/85 mm Hg) or less tight control (BP < 180/105 mm Hg) and followed up for a median of 8.4 years. The two main randomized treatments were the ACE inhibitor captopril or the beta-blocker atenolol, which were equally effective antihypertensive agents. The study showed that tight control of BP in diabetics is more beneficial in terms of clinical endpoints than the less tight control of blood pressure. Also, BP lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications.

Hence, this study suggested that BP reduction in itself might be more important than the treatment used.

Some interesting observations were:

1. Favourable trends with the beta-blocker for all seven primary clinical end-points as compared to captopril (Table 2).

2. The absence of a heart failure problem with the beta-blocker (indeed, compared to the beta-blocker there was a non- significant 21% excess in the captopril group).

3. That the well known anti-ventricular arrhythmic properties of beta-blockers may have been associated with the non- significant 142% excess (compared to the beta-blocker) in sudden deaths in the captopril group.

4. The fear of a beta-blocker causing, or worsening, peripheral vascular disease was not borne out, indeed there was a non-significant 48% excess of amputations in the captopril group.

5. The change in albuminuria and serum creatinine over the 9-year observation period was the same in both drug groups.

6. Glycated hemoglobin (HbA1c) was significantly higher in the beta-blocker group in the first 4 years, but not in the last 5 years of observation.

7. Hypoglycemic problems were the same in both drug groups. However, patients in the atenolol arm did not require an additional hypoglycemic medication more often than captopril patients (81% of the time, compared with 71%).

 

Cardioprotective role of beta-blockers in diabetic survivors of MI:
Collective evidence

Diabetic patients are particularly vulnerable in the post-infarction period and have a high mortality. This may be due to more extensive coronary disease, or a tendency to react more adversely to acute myocardial infarction. It is, therefore, of interest that in spite of their possible unwanted metabolic effects, there is evidence that in diabetic patients, the cardioprotective effect of beta-blockers is greater than in non-diabetic patients.2

Acute studies2
Diabetes subgroup analysis of the ISIS-1, Metoprolol in Acute Myocardial Infarction (MIAMI) and Goteberg Metoprolol Trial have revealed that mortality rates were significantly lower in the beta-blocker group as compared to the placebo group. The results of these studies are summarized in Figure 2.

Long-term studies 2
Analysis of diabetic patients in the Norwegian Timolol Study, Beta-blocker Heart Attack Trial (BHAT) study and a study conducted by Kjekshus and colleagues have shown the survival benefits with beta-blockers. The results of these studies are summarized in
Figure 3.

The favourable impact of beta-blockers in diabetic patients was achieved in spite of the poor risk factor profile generally associated with poor outcomes, including variables
such as advanced age, previous myocardial infarction and angina, radiological evidence of pulmonary congestion, and greater use of diuretics and digitalis.2 A meta-analysis of randomized, controlled, post myocardial infarction studies revealed that chronic beta-blockade was associated with an impressive 48% reduction in mortality in diabetics compared to 33% in non-diabetics (Figure 4).6

Thus, though diabetic patients have been considered less suitable for treatment with beta-blockers, concerns over negative metabolic effects should not be considered a contraindication to the use of selective b1-blockers in the post infarction period.

Indeed, data from the above post-infarction studies suggest a key role for beta-blockers in post-myocardial infarction patients with diabetes.

Inference from evidence

This article is an argument for not routinely withholding a proven effective therapy from patients just because they are diabetic. Physicians are reluctant to prescribe beta-blockers to diabetic patients because of their negative impact on glycemic control. However, there is little evidence to support the assertion that b-blockers should routinely be contraindicated in patients with type 2 diabetes mellitus. b-blockers have few clinically significant effects on hypoglycemic awareness and recovery, insulin resistance or lipid profiles in these patients. However, these possible negative effects can be minimized by the use of selective b1-blockers. Moreover, when patients with diabetes mellitus are treated with b-blockers for hypertension, or for the secondary prevention of MI, they benefit as much if not more than patients without diabetes mellitus. Indeed, there may be circumstances when b-blockers should be the first choice of treatment in patients with diabetes mellitus, e.g. those with hypertension and associated coronary artery disease.

Importantly, as per the latest American Diabetes Association guidelines for clinical management of diabetes, 2003, beta-blockers, among other drugs, have been recommended as the initial agents for diabetic hypertensives. The guidelines also affirm that in diabetic patients with recent myocardial infarction, beta-blockers should be considered to reduce mortality.7

The benefits in terms of important clinical end points appear to outweigh any possible adverse effects and favour the use of b-blockers. Hence, beta-blockers should no longer be considered routinely contraindicated in the presence of diabetes and to do so denies high-risk patients the opportunity to benefit from a therapy proven to decrease mortality, stroke and myocardial infarction.

Bibliography:
1. JIMA 2002; 100(3): 144-148
2. Diabetic Medicine 1994; 11: 137-144
3. Cardiovascular Drugs and Therapy 1999; 13: 435-439
4. European Heart Journal 2000; 21(5): 354-64
5. Drugs 2001; 61(4): 429-435
6. Cardiovascular Drugs and Therapy 2002; 16: 457-470
7. Diabetes Care 2003; 26(Suppl 1): S1-S156

Optimizing current beta-blocker therapy:
The introduction of extended-release metoprolol

Metoprolol Extended-Release (Metolar XR) recently introduced in the Indian market, is a once-daily formulation of the cardioselective lipophilic b1 receptor blocker.

• The extended-release metoprolol formulation produces a superior b1-blocking effect at 24 hours and over a period of 24 hours as compared to conventional metoprolol and atenolol, with lesser plasma fluctuations.
  
• It has shown a greater improvement in exercise duration and time to onset of angina as compared to conventional metoprolol.
  
• It significantly reduced number and duration of silent ischaemic episodes as compared to diltiazem. In patients with acute myocardial infarction, metoprolol extended-release has shown to improve ejection fraction and peak exercise capacity.
  
• Metoprolol extended-release also provides an antihypertensive effect superior to conventional beta-blockers. Studies have also shown that metoprolol extended-release exerts antiatherosclerotic effects and reduces the rate of progression of carotid intimal medial thickness and incidence of cardiovascular events.
  
• The incidence of fatigue and adverse effects on pulmonary function is also lesser with extended-release metoprolol as compared to atenolol.

The effects of metoprolol extended-release on glucose metabolism have compared favourably with those produced by atenolol, conventional metoprolol and long acting propranolol in placebo-controlled trials of healthy volunteers. All beta-blockers reduced the magnitude of the mean increase in plasma glucose levels induced by
b-agonist in healthy volunteers relative to placebo but the effect of metoprolol extended release was significantly less than that of atenolol. In another study done to evaluate the effects of b-blockade on insulin-induced hypoglycemia, heart rate increased from baseline with placebo (10 beats/min) and metoprolol-extended release (11.3 beats/min), whereas it was unchanged with atenolol and decreased with long acting propranolol (8.7 beats/min).

Drugs 1992; 43(3): 382-414