BETA BLOCKERS: AN IMPORTANT THERAPEUTIC MODALITY
FOR HYPERTENSIVE DIABETICS
Rehan and Khurram Nasir*
Research Centre, Pakistan Medical Research Council, Fatima Jinnah Medical
College, Lahore and *Department of Cardiology, John Hopkins University, Baltimore,
Diabetes mellitus and hypertension are amongst the
most common non-communicable diseases in Pakistan effecting nearly 2.7 and 10.8
million individuals respectively1. Both diseases are risk factors for
cardiovascular disease and death2. The prevalence of hypertension is
double among diabetics as compared to non-diabetics in the western world3.
Similar findings have also been reported from Pakistan4. The risk of
Cardio-vascular death in a hypertensive diabetic is twice that of a non-diabetic
hypertensive and four times that of a non-diabetic without hypertension5.
However it is distressing to know that a very low percentage of the Pakistani
population is aware as well as treated for these conditions1.
(β-blockers) are well established in the treatment of coronary heart
disease and hypertension6. However until recently they were
considered relatively contraindicated among diabetic patient7-10.
A recent meta-analysis by Psaty et al11, which was based on
the results of 18 Randomized Controlled Clinical Trials with 50,000 patients,
indicated that low dose thiazides (diuretics) and β-blockers are more
effective as compared to other agents in reducing total mortality,
cardiovascular mortality, stroke and myocardial infarction in individuals with
hypertension. The results of this meta-analysis make β-blockers potentially
a drug of choice among diabetic individuals with hypertension. Prospective
studies have, however, indicated an increased risk of mortality in diabetic
patients treated with diuretics12,13. As a result of these findings,
the use of diuretics as the first line treatment for hypertension in diabetes
mellitus has not been recommended14.
commentary aims to critically assess the common misconceptions held regarding
the use of β-blockers among diabetic hypertensive patients and to explore
the recent literature on use of β-blockers among hypertensive diabetic
A review of the relevant literature shows that the most common misconceptions about the use of β-blockers among
diabetic hypertensive patients are (1)
fear of developing Insulin resistance or hyperglycemia (2) masking of
hypoglycemic symptoms and (3) development of lipid abnormalities.
Insulin resistance or hyperglycemia
Increased insulin resistance with subsequent increased
blood glucose levels are frequently cited as an argument in favor of withholding
β-blockers from patients with diabetes mellitus. This impression is usually
based on two major studies conducted in early eighties; MRC Mild Hypertensive
Study15 and Beta Blocker Heart Attack Trial Research Group (BHAT)16.
MRC Mild Hypertensive Study15 indicated that non-selective β-blockers
tend to cause a small increase in blood glucose while Beta Blocker Heart Attack
Trial Research Group (BHAT)16 reported an increased prescription of
hypoglycemic agents in the Propranalol treated group. This resistance appears to
be the result of decreased β2-stimulated insulin secretion and
partly by reduced peripheral uptake of glucose17. This effect is
diminished with the use of beta selective agents18, especially if
concomitant changes in potassium and weight are avoided19. Although
this effect seems potentially important, there is little evidence that it is
clinical problem. Jonas et al followed a prospective cohort of 2,723 patients
with diabetes mellitus and established Coronary Artery Disease (CAD), and found
that patients on β-blockers achieved the same levels of glycemic control
and had a lower mortality, as compared to diabetics not using β-blockers20.
The UK Prospective Diabetes Study Group (UKPDS), whose results were published in
1998, has shown no difference in HbA1C levels between Atenelol (β-blockers)
and Captopril (ACE Inhibitor) groups, indicating comparable glycemic control21.
Masking of hypoglycemic symptoms
One of the most widely used reason for withholding
beta blockers for use in diabetic patients is that it may mask the symptoms of
hypoglycemia, which may prove fatal11, 13, 14, 18. This action is
mainly a characteristic of non-selective β-blockers by delaying the return
of low blood glucose to normal, along with modifying hypoglycemic signs and
symptoms23. However, the fact is ignored that hypoglycemic
unawareness to a level that may prove dangerous is a problem only in a small
number of patients with IDDM. Apart from this, the use of selective β1-blockers
reduces this concern further5, 13, 18. A prospective study of 778
elderly diabetic patients with hypertension and CAD found no increased risk of
hypoglycemia with use of beta-blocker 24. UKPDS also, in a nine-year
follow-up comparing the efficacy of Propranalol with Captopril, found no
difference between the number and severity of hypoglycemic events in either
treatment arms21, which should be a sufficient evidence to clear this
Changes in plasma lipid levels are also one of the
grounds for withholding β-blockers in diabetic patients. β-blockers
have little effect on LDL cholesterol, but do increase plasma VLDL as well
triglyceride levels, along with lowering HDL concentration25. Kasiske
et al, in a meta-analysis that included 474 trials found that use of β-blockers
is associated with an increase of triglycerides by 30mg/dl and decrease of HDL
cholesterol by 4 mg/dl on average26. This negative surrogate end
point (a lab measurement or a physical sign used as a substitute to a clinical
endpoint) has been a strong argument used to withhold β-blockers in
diabetic patients. These changes are more apparent with non-selective
beta-blockers, which may be due to the interference with peripheral lipoprotein
lipase, an enzyme responsible for the removal of endogenous triglycerides13.
However, the clinical significance of β2-blockade on changing
lipid levels is not clear, as non-selective agents such as Timolol and
Propranalol have been found very effective in reducing post-MI mortality and
re-infarction27, a benefit that is undiminished in the presence of
adverse changes in lipid levels28. Samuelsson et al in a prospective
study of 686 hypertensives, of which 76% used β-blockers, found that
although baseline triglyceride level elevation predicted future CVD events,
treatment induced hypertriglycedemia (>15 years of follow-up) did not add to
the initial risk29. However, even if this argument cannot eliminate
the concern regarding these adverse surrogate endpoints, the newer β-blockers
such as Labetalol, Acebutalol, Carvedilol and Bisprolol could be considered. It
has been observed that blood lipid level changes with these agents are minimal
or absent30, 31. The use of these agents is favored since β1-
blockade appears to be the active ingredient in cardiovascular protection, and
their use can also prevent the emergence of the adverse surrogate endpoints by
non selective beta blockade.
Apart from blood pressure lowering effect, β-blockers
have anti-anginal, anti ischemic and anti-arrhythmic properties, which have been
effective in reducing CHD events and deaths as shown by a number of studies32,
33, 34. Yusuf et al in a meta-analysis demonstrated 20-25% reduction in
recurrent CHD events and mortality in post-MI patients27.
Interestingly Gunderson et al showed a greater benefit derived by diabetic
patients in a secondary prevention trial of myocardial infarction as compared to
non-diabetics35. Such evidence is compelling to re-think that the
potential role of β-blockers in treatment of diabetic hypertensive patents.
Few would now disagree that β-blockers have a
useful role in the treatment role of heart failure, which was regarded a
contraindication until fairly recent times. However, the role of beta-blockers
regarding the treatment of hypertensive diabetics is still emerging. There has
been a long held bias against the use of β-blockers in diabetes, especially
in favor of ACE- inhibitors. The more frequent and liberal use of ACE inhibitors
in diabetes mellitus is mainly due to a) their insignificant effects on
triglcerides, HDL and LDL levels36, b) delayed diabetic nephropathy37
which appears to be an independent effect of blood pressure control38,
and c) ability to reduce insulin resistance36. Thus, it has been
advocated that ACE inhibitors should be the first line therapy for hypertension
in diabetic patients, due to the lack of ACE inhibitors effecting the above
mentioned surrogate end-points. Study results favoring more liberal use of
beta-blockers in type II diabetics come from the UKPDS21, 39. The
UKPDS study has shown that tight control of hypertension in diabetic patients
resulted in fewer cardiovascular events and is more important than glycemic
control in reducing CVD events and mortality. Importantly, β-blockers were
as effective as ACE inhibitors, and there were trends favoring the use of β-blockers,
such as fewer myocardial infarctions, fewer strokes and micro vascular diseases,
and lower total mortality21 in
β1 selective blockade appeared to be the active ingredient for
review does not advocate the use of β-blockers in every hypertensive
diabetic. Reviewing the results of the HANE study41 in 886 young to
middle aged men and women (21-70 years) and the Veteran Affairs Cooperative
study in 1105 men42, Atenolol was found to be best for younger
individuals (<60 years) while hydrocholorothiazide and dialtizam were best
for older individuals with hypertension. As
a result β-blockers should not be the first line therapy for older
hypertensives. These conclusions also apply to elderly hypertensive diabetic
the UKPDS study the most common reason for non-compliance with Atenelol was
brochoconstriction21; a risk which is greatest with the use of
non-selective agents without intrinsic symptomatic activity23.
Although this risk is minimized with the use of highly selective β1 blockers,
but patients are not totally safe from reversible airway changes43.
In hypertensive diabetic patients with severe airway conditions, alternative
therapy should be offered. Similarly in those patients with IDDM who suffer from
hypoglycemic symptom unawareness, β-blockers may be contraindicated with an
ACE inhibitor or calcium channel blocker considered12-14. In patients
with diabetic nephropathy (mainly seen in IDDM patients), ACE inhibitors are
recommended to delay the onset of end stage renal-disease44, 45.
However β-blockers can now be considered for the same role as the results
of SOLVD Heart Failure Study46 indicated that β-blockers offered
more reno-protection as compared to ACE inhibitor. Finally among patients with
autonomic dysfunction, the use of β-blockers may be challenginge13, 14.
important aspect to consider is the quality of life for the patient.
Hypertension in most cases, even associated with type II diabetes is
asymptomatic. Thus it is very important to ensure compliance, which can be
significantly enhanced with agents that do not produce side effects that impairs
quality of life40. Although Croog et al looking into quality of life
with antihypertensives demonstrated that propranalol, but not captopril
decreased quality of life47, many similar studies comparing beta
selective agents with ACE inhibitors found no difference between their effects
on quality of life48-50.
of surrogate end points has lead to hesitancy for using beta-blockers in
diabetic hypertensives. Despite widely held beliefs, the literature supports the
notion that β-blockers should be among the preferred therapy for
hypertensive diabetic patients. They cause the reduction of the most important
complications of diabetes with hypertension, such as CVD events, strokes and
mortality. This paper calls on practitioners to reconsider the role of β-blockers
on their menu of options for hypertensive diabetics.
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