Hypertension and Diabetes: The Choice of Antihypertensive
Therapy
Dr. C.R. Kumana, BSc, MB, FRCP
Reader in Medicine
Clinical Pharmacologist
University of Hong Kong
The choice of antihypertensive therapy in diabetes
mellitus constitutes a very large topic which cannot be
covered comprehensively in the space of this article.
Under the circumstances, there will be a focus on
certain aspects of antihypertensive drug therapy with
particular reference to a) the treatment of mild to
moderate hypertension (not severe hypertension or
emergency treatment), b) issues which are clinically
relevant to general practitioners and c) popular first
and second line agents (viz;- adrenergic antagonists,
thiazide diuretics, and vasodilators), as are commonly
used in the stepped care approach to antihypertensive
treatment.
Adrenergic Antagonists
Experimental data from animals and in vitro studies
suggest that insulin secretion is enhanced in the
presence of beta-2 receptor stimulation and diminished
when alpha-2 receptors are stimulated. One might
therefore anticipate that beta-2 receptor antagonism
might lead to diminished insulin release, higher blood
sugars and diminished glucose tolerance, and vice versa
after alpha-2 receptor antagonism. Fortunately, many
adrenergic antagonists have a negligible net effect on
blood sugar. This seems to be the case for:—
(1) Central Adrenergic Inhibitors (which reduce
peripheral sympathetic tone) e.g. alpha methyldopa,
clonidine,
(2) Adrenergic Neurone Blockers (which deplete
presynaptic noradrenaline) e.g. reserpine, guanethidine
and
(3) Alpha-1 Blockers e.g. prazosin
Though objective as opposed to anecdotal data about
the use of these classes of drugs in diabetes are scarce,
it is widely accepted that they do not have clinically
important effects on glucose tolerance and are therefore
not contraindicated in diabetes.
Beta-Adrenergic Blockade
Anti-hypertensive treatment of diabetics with these
drugs is somewhat more complex.
Influence on Glucose Tolerance: In a placebo
controlled study of a beta-blockade in 20 hypertensive
diabetics controlled by diet and/or hypoglycaemic
agents (Wright et al 1979) there were only trivial
increases in mean blood sugar (fasting, pre lunch and
mid afternoon) after one month's treatment with
propranolol or metoprolol according to a double blind
protocol. In individual patients however, considerable
hyperglycaemia occurred, and these outliers were
mainly responsible for the small effect on mean blood
glucose. Several other studies have reported similar
results. It is therefore accepted that in the majority of
diabetics beta-blockade usually produces no clinically
significant impairment of glucose tolerance but a few
individuals experience important increases in blood
glucose. As to why hyperglycaemia is occasionally
encountered, there are many uncertainties (viz. the
importance of selective versus non-selective beta-
blockade, inter-relationship with the arachidonic acid
cascade, and the role of 1 verses d propranolol).
Beta-Blockade and Hypoglycaemia: The normal
response to clinically significant hypoglycaemia is
sympathetic stimulation, largely mediated through the
release of adrenaline. This gives rise to widespread
alpha and beta-receptor stimulation, which no doubt
accounts for many of the prodromal symptoms (e.g.
palpitations, tremor). Metabolic consequences
(probably mediated through stimulation of alpha-2 and
beta-2 receptors in the liver) include increased
glycogenolysis and gluconeogenesis, both of which
tend to restore the blood sugar. It is well known that
diabetic patients treated with sulphonylureas or insulin
are subject to hypoglycaemia, and it should be realised
3551
Hypertension and Diabetes
that beta-blockade can interfere with the consequences
in at least 3 different ways:—
1) Beta-blockade Masks the Prodromal
Symptoms of Hypoglycaemia. In particular, tremor,
palpitation, hunger pangs and hyperventilation
become diminished or are not experienced at all,
whereas sweating (a cholinergically mediated res-
ponse) may be exaggerated. Clearly, all diabetic
patients receiving hypoglycaemic agents should be
warned about this effect and asked to pay special
Figure 1: Rate of Increase in Blood-Glucose Levels after Insulin (n = 7)
400+
S 300-•
100
20 40 60
Time (min) from nadir
Modified Figure 2, Lger et al 1979, Lancet 1, 458-62
recovery from hypoglycaemia by inhibiting
glycogenolysis and gluconeogenesis, this effect is
seldom important clinically, except when there is
additional hypoglycaemic provocation, e.g. severe
exercise, and end stage renal failure.
3) Exaggerated Hypertensive Responses. Many
well controlled studies in normal volunteers and
hypertensive patients show that infusion of adrenaline
(which stimulates alpha-receptor mediated
vasoconstriction as well as beta receptor mediated
vasodilatation) reduces net peripheral resistance
(Figure 2). This is usually associated with a fall in
diastolic and mean blood pressure and an increase in
heart rate. After giving a non-selective beta-blocker
such as propranolol (which inhibits beta-2 receptor
3552
attention to sweating even without the other sympt-
oms. Perhaps,betablocking drugs should be avoided
altogether in patients who are frequently prone to
hypoglycaemia.
2) Non-selective Beta-blockade Delays the
Restoration of Blood Sugar. Whereas the relatively
selective beta-blockers (e.g. metoprolol and atenolol)
usually do not have any discernable effect, propranolol
tends to interfere with the compensatory metabolic
responses (Figure 1). Whilst it is conceded that beta-
blockade (especially when non-selective) slows the
Placebo
Metoprolol
Propranolol
80 100 120 140 160 180 200
mediated vasodilatation), adrenaline administration
results in unopposed alpha receptor mediated
vasoconstriction becoming unmasked, resulting in a
rise of peripheral resistance. Consequently, diastolic
and mean blood pressure increases and heart rate
decreases (presumably due to a reflex effect). After
administration of a relatively selective antagonist like
metoprolol, vascular beta- receptors appear relatively
spared and the haemodynamic response to adrenaline
resembles that in the control state. Not surprisingly,
after insulin induced hypoglycaemia which also
releases adrenaline, diastolic blood pressure generally
falls. Furthermore, many studies have confirmed that
after pre-treatment with propranolol, similar degrees
of hypoglycaemia elevate diastolic pressure (Figure 3).
Moreover, though the mean haemodynamic responses
(turn to page 3554)
Hypertension and Diabetes

Figure 2: Haemodynamic Responses to Adren- are generally small, they tend to be relatively larger
aline on and off Beta-Blockers in the presence of non-selective as opposed to selective
beta-blockade and individual patients receiving non-
Mean artenal selective drugs like propranolol can experience very
Heart rate blood pressure
beats/min mm Hg serious elevations in blood pressure.
80-r

Thiazide Diuretics
60- 90-
It is well known that thiazide (and loop) diuretics
40- 70- are diabetogenic. This effect may be partly attributed
Peripheral Diastolic
to diminished release and reduced sensitivity to insulin.
resistance U blood pressure In part this may result from the slight lowering of
70 n mm Hg
plasma potassium levels induced by these drugs.
100-1
Moreover, diazoxide (a non-diuretic thiazide
50-
vasodilator) commonly gives rise to hypokalaemia and
75- hypoglycaemia and very rarely thiazides have been
30-
implicated in causing pancreatitis. Though the
10- 50- hypokalaemic effect of diuretics is generally considered
to be trivial, in several recent studies (MRFIT, MRC
Before During Before During trial in mild hypertension) many reservations have been
Adr infusion Adr infusion
aired concerning its epidemiological significance.
metoprolol: 10 mg i.v. Interestingly, the use of potassium supplements can
propranolol: 5 mg i.v.
control correct the diabetogenic effect of these drugs.
It is interesting to compare the adverse effects and
Modified from Johnsson 1975, Acta Pharm et Tox, 36 Suppl V, 59 relative contraindications of thiazide diuretics and beta

Figure 3: Blood Pressure Responses to Insulin/

Hypoglycaemia in Seven Diabetic
Patients

180 Placebo Metoprolol Propranolol

Mean ± SEM
160 . ,

140

100 .

80 .

60 .
"E.
5 min Nadir 5 min Nadir 5 min Nadir

Modified Figure 4, Lager et al. 1979, Lancet 1, 458-62

3554

blockers pertinent to their use in diabetes (Table 1).
As has already been mentioned, beta-blockers are
relatively contraindicated in patients subject to
hypoglycaemia (brittle diabetes). In considering some
of the other listed side effects and contraindications,
it is useful to refer to the results of the MRC trial in
mild hypertension (1985). The latter was a randomised
single blind placebo controlled trial carried out in
general practice and involved more than 17,000 mild
hypertensives screened from clinic patients and
excluded diabetics. Compared to the placebo group,
withdrawal of trial medication due to diabetes (about
0.75% of cases) in patients receiving bendrofluazide
was threefold more common, and due to impotence in
men (about 1.5% of cases) eight-fold greater.
Correspondingly withdrawal from propranolol due to
Raynauds phenomenon or peripheral vascular insuffi-
ciency though rare (about 0.5%), was at least 14 fold
more common than on placebo. In this investigation,
possible symptoms due to vasomotor instability
(dizziness, nausea, headache) were no more common
in patients taking diuretics as opposed to beta-blockers,
but in patients with diabetics with autonomic
neuropathy, it is likely that diuretics would produce
such side effects more readily. According to the MRC
trial and other studies, propranolol therapy definitely
has an unfavourable influence in smokers.
Beta-Blockers
Thiazide Diuretics
Raynauds & Peripheral Diabetes
Vascular Disease Impotence (men)
Hypoglycaemia
Ventricular tachyarrhythmia
(brittle diabetes)
Hypokalaemia
Smoking
Dizziness, Nausea,
Headache
Adapted from MRC Mild Hypertension trial, 1885, BMJ,
291, 97-104.
Table 1: Adverse Effects/Relative Contraindications
Pertinent to Diabetes
Calcium Antagonists
Since diabetic patients are subject to both
hypertension and angina, there is considerable interest
Vol. 10 No. 12 December 1988
in treating them with calcium channel blockers.
However, those with autonomic neuropathy may
experience excessive postural symptoms (headaches,
palpitations, flushing and oedema) due to the
vasodilator properties of these drugs. Based on ex-
perimental data there are also concerns that calcium
antagonists alter glucose homeostasis. Increases in
blood glucose stimulate pancreatic beta cells to release
insulin by a process that is calcium influx dependent.
Therefore, on theoretical grounds calcium antagonists
may interfere with the pancreatic response to increases
in blood glucose. Clinical information regarding this
possibility remains meager, partly because the various
calcium antagonists in current use are dissimilar.
Moreover, the "studies" often referred to are of quest-
ionable design (non-blind, non-randomised, anecdot-
al, small numbers). Nevertheless, most suggest that
there is no important effect but a minority of investi-
gators have reported considerable elevations in blood
glucose levels after treatment with nifedipine. How-
ever the latter effects may be related to the duration of
therapy and the doses involved.
With respect to the risks of developing atheromatous
complications in hypertensive diabetics, in contrast to
some of the commonly used thiazide diuretics and beta-
blockers (Table 2), calcium channel antagonists do not
seem to exert an unfavourable influence on plasma lipid
profiles. Despite this apparent advantage it should be
appreciated that calcium channel blockers (as opposed
to beta-blockers) have not yet been shown to improve
outcome from cardiovascular disease.
Conclusion
Regarding the choice of antihypertensive drug
therapy in diabetes it is clear that many drugs have
altered risk/adverse effect profiles in diabetic patients.
However, any additional unfavourable influence from
these drugs due to diabetes is usually minimal. In a
small minority of diabetic individuals, certain
risks/adverse effects could assume clinical significance.
Whilst no antihypertensive drug is completely contrain-
dicated in diabetes, it is useful to take account of
individual patient characteristics when considering
therapy. In patients with brittle diabetes or peripheral
vascular disease, beta blocking drugs (especially non-
selective agents like propranolol) are relatively
3555
(turn to page 3558)
Hypertension and Diabetes

Total LDL HDL

Cholesterol Triglyceride

Beta-Blockers
Non-selective +
Relatively /}, ±
selective
Non-selective
with ISA

Diuretics
Hydrochlorothiazide
(50-100 mg/day)
Chlorthalidone
(12.5-100 mg/day)
Clopamide
(5 mg/day)
Indapamide

Mean duration of treatment = 13-26 weeks, ± = No significant change, + = Increase, — = Decrease

Table 2: Plasma Lipid Changes Following Antihypertensive Treatment with Beta-Blockers and Diuretics

contraindicated. In those whose diabetes is poorly Further Reading

controlled or who experience impotence or postural
symptoms, it may be prudent to avoid thiazides. As
a general rule diabetics starting antihypertensive' drug
treatment need to be carefully monitored. If
appropriate, they may require adjustment of their diet
and/or antidiabetic drug dosage. Rarely, it may be
necessary to select an alternative antihypertensive drug.
McKenney JM, Goodman RP, Wright JT: 1985 Clinical Pharmacy 4
649-56. Use of Antihypertensive Agents in Patients with Glucose
Intolerance.
Editorial Review: 1985 Journal of Hypertension 3 297-306.
Antihypertensive Treatment and Serum Lipoproteins.
Kendall MJ, Horton RC, Chellingsworth MC: 1986 Journal of Clinical
& Hospital Pharmacy, 11 175-80. Calcium Antagonists and Glycaemic
Control.
Kumana CR: 1987 Drugs for Heart Disease, 2nd Edition, (edited by
J. Hamer), publishers Chapman & Hall Ltd, Chapter 2, 29-75 on 'Beta
Adrenergic Blocking Drugs'.

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