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REVIEW

Antihypertensive medications and blood sugar:

Theories and implications
David F Blackburn PharmD1, Thomas W Wilson MD FRCPC2

DF Blackburn, TW Wilson. Antihypertensive medications and

blood sugar: Theories and implications. Can J Cardiol
2006;22(3):229-233.
Increased rates of diabetes have been reported with thiazide diuretics
and beta-blockers, but not with angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers or calcium channel blockers.
These observations are important because significant glycemic effects of
drugs may be a source of accelerated cardiovascular risk that is not
detectable during restricted clinical trial follow-up periods. The extent
to which diabetes is affected by these medications remains unclear, as is
the precise mechanism by which diabetes is promoted. However, several plausible theories are presented herein. Although drug-induced diabetes has been a concern for several years, not enough is information is
available to influence prescribing for the majority of patients. The number one priority should be controlling blood pressure in a timely manner.

Key Words: Diabetes mellitus; Hypertension

he cardiovascular benefits of reducing blood pressure (BP)

have been well documented (1-4) and usually occur independently of the specific antihypertensive agent used (3-7). As
a result, clinical practice guidelines suggest that several antihypertensive classes are acceptable first-line agents for the management of uncomplicated hypertension. These classes include
thiazide diuretics, angiotensin-converting enzyme inhibitors
(ACEIs), angiotensin receptor blockers (ARBs), beta-blockers
and calcium channel blockers (8,9). Despite their similar cardiovascular benefits, however, antihypertensive agents clearly
exhibit distinct adverse effects.
One major difference among antihypertensive agents is the
potential to adversely affect glucose homeostasis. Certain
agents have been associated with insulin resistance and diabetes mellitus, which are independent predictors of cardiovascular morbidity (10-13). Two reports (14,15) have suggested
that elevated serum glucose concentrations during antihypertensive treatment predicts future cardiovascular events, while
another report (16) has found that diabetes occurring during
antihypertensive therapy is inconsequential. Of course,
patients who develop diabetes mellitus may require more
intensive monitoring and more medications to achieve strict
glycemic, cholesterol and BP targets (8,10,17,18).
In this narrative review, we will summarize the various
mechanisms by which antihypertensive medications may cause
diabetes, report on the results of several notable clinical trials
and review the potential long-term implications of developing
diabetes due to antihypertensive therapy. For a comprehensive
summary of available evidence, we refer readers to an excellent
systematic review that has been recently published (19).

Antihypertenseurs et glycmie : Thories et

rpercussions
Une augmentation des taux de diabte a t signale avec les diurtiques
thiazidiques et les bta-bloquants, mais non avec les inhibiteurs de
lenzyme de conversion de langiotensine, les bloqueurs des rcepteurs de
langiotensine ou les anticalciques. Le phnomne est important puisque
les effets glycmiques marqus de ces mdicaments peuvent entraner une
exacerbation du risque cardiovasculaire difficilement dcelable compte
tenu de la brivet des suivis lors des essais cliniques. On ignore encore
quelle est la porte exacte de ces mdicaments sur le diabte et par quel
mcanisme prcis ce dernier serait ainsi favoris. Par contre, plusieurs
thories plausibles sont prsentes ici. Bien que le diabte dorigine
mdicamenteuse suscite dj linquitude depuis quelques annes, les
donnes dont on dispose actuellement sont encore insuffisantes pour que
lon puisse modifier les prescriptions remises la majorit des patients,
lobjectif numro un du traitement demeurant lobtention dans les
meilleurs dlais dune bonne matrise de la tension artrielle.

MECHANISMS OF ADVERSE GLYCEMIC EFFECTS

Various theories about the mechanisms of antihypertensiveinduced glycemic defects have been postulated. Few of these
theories have been confirmed and some are conflicting. In
general, postulated mechanisms can be classified into four categories: effects on peripheral blood flow, effects on the insulin
receptor, effects on the liver and effects on insulin release
(Figure 1).

Figure 1) Summary of the metabolic abnormalities that contribute to

hyperglycemia. Reduced blood flow to tissues, increased hepatic glucose
production, impaired insulin secretion, and insulin resistance caused by
receptor and postreceptor defects all combine to generate the hyperglycemic state. Reproduced with permission from The American
Diabetes Association (personal communication)

1College of Pharmacy and Nutrition; 2College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan
Correspondence: Dr David F Blackburn, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon,
Saskatchewan S7N 5C9. Telephone 306-966-2081, fax 306-966-6377, e-mail [email protected]
Received for publication April 7, 2005. Accepted August 3, 2005

Can J Cardiol Vol 22 No 3 March 1, 2006

2006 Pulsus Group Inc. All rights reserved

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Improved peripheral blood flow to skeletal muscles is

thought to facilitate glucose disposal to the tissues. In this way,
medications such as alpha-blockers, which promote peripheral
vasodilation, may improve insulin sensitivity and glucose
uptake (20). Through the same mechanism, ACEIs or ARBs
may improve insulin sensitivity by reducing angiotensin IImediated vasoconstriction and/or increasing vasodilators such
as bradykinin, prostaglandins or nitric oxide (21,22).
Conversely, medications that reduce peripheral blood flow
could direct blood away from sites of glucose uptake, reducing
glucose disposal (20). Nonselective beta-blockers limit peripheral blood flow by reducing cardiac output, a beta-1-mediated
effect, and preventing peripheral vasodilation, a beta-2-mediated
effect (20,23). Beta-blockers with intrinsic sympathomimetic
activity are less likely than nonselective agents to reduce
peripheral blood flow because of neutral or stimulatory effects
on beta-2 receptors (20,23). Therefore, these agents may have
a reduced impact on glucose disposal and insulin sensitivity
compared with nonselective beta-blockers. Cardioselective
beta-blockers are also less likely to reduce peripheral blood
flow than nonselective agents; however, cardioselective betablockers still exhibit some glycemic adverse effects (23). In
support of the blood flow hypothesis is the observation that
reduced capillary density in skeletal muscle places individuals at
a greater risk for beta-blocker-induced glycemic effects (20,23).
Insulin sensitivity may also be altered through effects on the
insulin receptor or downstream signalling. Although few studies
have directly examined changes to the insulin receptor, it
appears that some antihypertensive agents may modify its activity. Hypokalemia has been linked to reduced insulin-receptor
sensitivity (24), but this theory has not been consistently supported (25,26). Various antihypertensive agents could alter glucose transport proteins (GLUT 1 and GLUT 4), tyrosine kinase
activity, or insulin receptor binding affinity. However, more
information is needed to evaluate these effects (21,27).
Two other potential sources of altered glucose control
include hepatic insulin resistance and impaired insulin release.
It has been suggested that thiazide diuretics promote hepatic
insulin resistance, resulting in continued hepatic glucose production despite rising serum glucose or insulin levels (24,28).
Although this effect has been observed with high-dose thiazide
diuretics, it is less apparent with lower doses (12.5 mg to 25 mg
of hydrochlorothiazide daily) used in current practice (28).
Inhibition of insulin release can lead to hyperglycemia, and
beta-blockers have long been considered to inhibit insulin
release through pancreatic beta-receptor blockade (29).
Similarly, diuretic therapy has also been associated with
impaired insulin release through depletion of serum potassium
(30). However, because insulin levels are higher than normal
in most patients with diabetes (23), this mechanism is unlikely
to be of major importance.

INCIDENCE OF DIABETES DURING

ANTIHYPERTENSIVE TREATMENT
Beta-blockers
In observational studies, thiazides (15,31,32) and beta-blockers
(25,29,31-34) have been most commonly linked to the development of diabetes mellitus. In one notable study suggesting
the harmful effects of beta-blockers, the Atherosclerosis Risk
In Communities (ARIC) study (29), over 12,000 nondiabetic
subjects were identified and followed prospectively. Among
subjects with hypertension at baseline, beta-blockers were
230

associated with an increased risk of diabetes development (hazard ratio 1.28, 95% CI 1.04 to 1.57), while thiazide diuretics,
ACEIs and calcium channel blockers did not exhibit such
effects. Three studies (25,33,34) have reached similar conclusions about the relative effects of beta-blockers and thiazide
diuretics, but these studies are less robust and provide no additional information. In a post hoc analysis of the Systolic
Hypertension in the Elderly Program (SHEP) clinical trial
(chlorthalidone versus placebo), the addition of atenolol to
chlorthalidone increased the rate of new-onset diabetes by
40% (16.4% versus 11.8% for chlorthalidone- and placebotreated patients, respectively) (16). There are, however, exceptions. In a recent study of elderly patients (at least 66 years of
age) receiving antihypertensive therapy (35), new-onset diabetes was not increased with any medication class.
Although most studies suggest that beta-blockers exhibit
significant glycemic effects, there is little information on the
differences between cardioselective and nonselective betablockers. Most reports only examine nonselective agents such
as propranolol (8,33,34), and others do not distinguish
between agents with and without beta-1 selectivity
(15,29,31,32,35). In addition, many of these studies neglect to
closely document the extent of drug exposure.
Several clinical trials have evaluated the short-term effects of
beta-blockers with intrinsic sympathomimetic activity (dilevalol [36] and pindolol [37]) or alpha-blocking effects
(carvedilol [38,39]). Consistent with the blood flow hypothesis,
these agents appear to have a reduced impact on insulin sensitivity compared with nonselective (37) and cardioselective
agents (36,38,39), presumably because of favourable effects on
peripheral blood flow. Considering the fact that cardioselective
beta-blockers are used extensively in uncomplicated hypertension, further study is needed to quantify their glycemic effects.
Thiazide diuretics
In 1981, a randomized, controlled trial from the Medical
Research Council (40) suggested that thiazide diuretics exhibited significant adverse glycemic effects. Patients receiving
bendrofluazide developed more impaired glucose tolerance
than those receiving propranolol (15.4 versus 4.8 cases per
1000 patient-years, respectively). Although this difference was
striking, the dose of bendrofluazide was extremely high at 5 mg
twice daily. Currently used thiazide diuretics are administered
at a fraction of this dose.
To examine the effect of lower doses, Harper et al (28) randomly assigned 15 hypertensive patients to high-dose (5 mg)
or low-dose (1.25 mg) bendrofluazide for 12 weeks in a doubleblind, crossover study. No differences were observed for fasting
glucose, serum lipid values or peripheral insulin sensitivity;
however, endogenous (hepatic) glucose production was significantly greater in the high-dose group, suggesting that a reduction in hepatic insulin sensitivity had occurred.
Although high-dose thiazide diuretics are no longer used to
manage hypertension, glycemic adverse effects may still be a
consequence of low-dose agents. Recently, Verdecchia et al
(15) reported an increased rate of diabetes development in
patients receiving low-dose thiazides but not other antihypertensive agents, including beta-blockers. Also, three large,
prospective clinical trials have demonstrated definite adverse
effects of thiazides on glucose homeostasis (1,4,7). In the
SHEP trial (1), three years of low-dose chlorthalidone,
12.5 mg to 25 mg daily, was associated with a significant
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elevation in fasting glucose compared with placebo

(0.51 mmol/L versus 0.31 mmol/L, respectively; P<0.01) and a
significant increase in the incidence of diabetes (13.0% versus
8.7%, respectively; P<0.001) (16). In the recently published
Antihypertensive and Lipid-Lowering treatment to prevent
Heart Attack Trial (ALLHAT) (7), over 42,000 hypertensive
patients were randomly assigned to one of four groups:
chlorthalidone, amlodipine, lisinopril or doxazosin. Of the
three arms remaining after four years, the incidence of diabetes
was significantly higher in the chlorthalidone arm (11.6%)
than in the amlodipine arm (9.8%; P=0.04) and the lisinopril
arm (8.1%; P<0.001). Atenolol was allowed as add-on therapy
and may have influenced this outcome, but the proportion of
patients receiving it was not specified. A similar study of
hypertensive patients (4) reported a higher rate of new-onset
diabetes in patients receiving low-dose diuretic therapy than in
those receiving long-acting nifedipine (5.6% versus 4.3%,
respectively; P=0.02).
Many of these studies do not address the impact of initial
antihypertensive selection because most patients had previously
received antihypertensive therapy. Also, comparator groups
are clouded by the use of various agents as adjuvant therapy.
Although thiazide diuretics provide similar cardiovascular
benefits to other antihypertensive classes over the short-term
(7), some have expressed concern that new-onset diabetes
accelerates cardiovascular risk over the long-term (14,15).
Other agents
Three additional classes of medications ACEIs, dihydropyridine calcium channel blockers and ARBs are also considered
acceptable first-line agents in the management of patients with
uncomplicated hypertension (8). In contrast with beta-blockers
and thiazide diuretics, these agents have not been associated
with glycemic adverse effects. Calcium channel blockers are
generally thought to exhibit negligible effects on glucose
metabolism (35,41), and ACEIs/ARBs may actually have beneficial effects.
Support for a protective effect of ACEIs/ARBs comes from
the results of several prospective clinical trials. In the
Captopril Prevention Project (CAPP) (3), a randomized trial
comparing captopril with beta-blockers or diuretics in 11,000
patients with hypertension, the incidence of diabetes was
reduced by 20% in patients treated with captopril. Because
there was no placebo group, it is not clear whether the difference in diabetes development was a result of a protective effect
of captopril or a harmful effect of beta-blockers or diuretics. A
more recently published trial (42), the International
Verapamil-Trandolapril Study (INVEST), compared verapamil- and atenolol-based regimens in hypertensive patients
with stable coronary artery disease. In a post hoc analysis of
new diabetes occurring during this study, the addition of trandolapril appeared to confer a protective effect against diabetes
development. Another recent trial (43) in hypertensive
patients, the Valsartan Antihypertensive Long-term Use
Evaluation (VALUE) trial, enrolled 15,245 hypertensive
patients and demonstrated a lower rate of diabetes in patients
receiving valsartan than in those receiving amlodipine (13.1%
versus 16.4%, respectively; P<0.0001). Other studies (44,45)
have also indicated the protective effects of ACEIs or ARBs in
patients without hypertension.
Short-term studies have confirmed that ACEIs are less likely
to impair glucose metabolism than beta-blockers (26,46), and
Can J Cardiol Vol 22 No 3 March 1, 2006

some ACEIs have shown a protective effect compared with

placebo (21,47,48). Three similar studies by Fogari et al
demonstrated the protective effects of lisinopril (47), perindopril (48) and trandolapril (21) compared with placebo and
losartan, which had little impact on glycemic indexes.
However, it is unclear whether differences in dosing intensity
or BP control confounded the comparisons with losartan. In
contrast, losartan was associated with a reduction in new-onset
diabetes compared with atenolol in the prospective Losartan
Intervention For Endpoint reduction in hypertension (LIFE)
study (49); 241 (6%) and 319 (8%) new-onset diabetes cases
were reported for losartan and atenolol over an average follow-up
period of 4.8 years, respectively (hazard ratio 0.75, 95% CI
0.63 to 0.88; P=0.001).
It should be noted that hypertension itself is often an
insulin-resistant state, and that the incidence of diabetes in the
untreated hypertensive population is elevated (20). Therefore,
it is difficult to say whether beta-blockers and thiazides accelerate the development of diabetes, or whether ACEIs and
angiotensin receptor antagonists confer a protective effect.
Several ongoing studies are evaluating the use of ACEIs or
ARBs in patients with impaired fasting glucose or impaired
glucose tolerance. Ramipril is currently being studied in the
Diabetes Reduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial, valsartan in the Nateglinide
And Valsartan in Impaired Glucose Tolerance Outcomes
Research (NAVIGATOR) trial, and irbesartan in the
Irbesartan in the Treatment of Hypertensive Patients with
Metabolic syndrome trial. In addition, further analyses of the
ALLHAT study are expected to shed more light on the differences observed between lisinopril, amlodipine and chlorthalidone.

IMPLICATIONS OF GLYCEMIC ADVERSE

EFFECTS IN HYPERTENSIVE PATIENTS
It seems clear that glycemic adverse events occur with certain
beta-blockers or thiazide diuretics, at least to some extent.
However, it is not known whether these adverse effects are
responsible for new cases of diabetes in patients who would
have otherwise remained euglycemic, or whether the additional
cases are observed in those who are already predisposed to
developing diabetes. In the latter case, the incremental cardiovascular risk may be small because predisposed patients, such as
those with metabolic syndrome, already have a constellation of
risk factors that confer a significant cardiovascular risk, even
when their sugar concentrations are below the diabetic range
(50). This theory would explain why differences in new-onset
diabetes rates became smaller over the course of the ALLHAT
study (51). In the other scenario, the consequences of newonset diabetes may also be small if new cases of diabetes are a
result of isolated blood sugar elevations without the associated
metabolic abnormalities, such as dyslipidemia, insulin resistance and abdominal obesity.
Few studies have attempted to evaluate the consequences of
glycemic adverse effects caused by antihypertensive medications. Of the available reports, none have reduced confounding
factors sufficiently to allow for firm conclusions about the danger of this adverse effect. Dunder et al (14) found that elevated
levels of blood glucose were an independent predictor of
myocardial infarction in patients receiving antihypertensive
therapy, but not in normotensive patients. Although the
authors controlled for several important confounders, the effect
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of antihypertensive medication was not clearly distinguished

from hypertension because the control group was normotensive. Verdecchia et al (15) also found a link between new-onset
diabetes and cardiovascular events. In their observational study
of hypertensive patients, the cardiovascular event rate of those
developing new-onset diabetes during antihypertensive therapy
was almost identical to those patients with established diabetes
at baseline. Both groups (new-onset and established diabetes)
exhibited cardiovascular event rates that were significantly
higher than the rate for patients who remained euglycemic.
Assuming that many of these patients exhibited signs of the
metabolic syndrome, it is not surprising their cardiovascular risk
was high, even before the development of diabetes. In contrast,
long-term follow-up results of a previously published clinical
trial comparing chlorthalidone with placebo (SHEP) suggested
that new-onset diabetes occurring during active therapy was
not associated with increased mortality over a period of 14 years
(16). Data from this report are also preliminary because drug use
was unknown for the majority of the follow-up period.

SUMMARY
There is evidence indicating that thiazide diuretics and certain
beta-blockers exhibit adverse glycemic effects. In theory, these
effects may be associated with an accelerated risk for cardiovascular events in the long term, beyond the follow-up of
prospective clinical trials. However, the extent to which these
adverse effects increase long-term cardiovascular safety
remains theoretical, and the mechanisms have not been confirmed. Furthermore, avoiding valuable antihypertensive
agents like thiazide diuretics may be risky if this means delaying

the time taken to achieve BP control. A recently published trial

(43) provides evidence for the importance of prompt control of
BP, and we have found that low-dose thiazides, at least in combination, are often required to achieve BP control in the
majority of our patients. Accordingly, avoidance of thiazides
could delay or prevent adequate BP control in many patients
and unnecessarily increase cardiovascular risk over the short
term. As for the long-term consequences of glycemic adverse
effects, it is our view that these effects are small and limited to
blood glucose only. It is doubtful to us that these effects influence the constellation of metabolic risk factors that play a significant role in a patients cardiovascular risk. Future
prospective trials may shed more light on the consequences of
antihypertensive-induced glycemic effects and their complications; however, current evidence suggests that prompt BP control with established agents is of paramount importance.
NOTE: Since the acceptance of this manuscript, the results of
Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure
Lowering Arm (ASCOT-BPLA) (52) have been published. In
this prospective study, almost 20,000 hypertensive patients were
randomly assigned to either a beta-blocker/thiazide diuretic or a
calcium channel blocker/ACEI-based regimen. During a median
follow-up of 5.5 years, the beta-blocker/thiazide group developed
new-onset diabetes at a higher rate than the calcium channel
blocker/ACEI group (8.3% versus 5.9%, respectively [hazard
ratio 0.70, 95% CI 0.63 to 0.78, P<0.0001]). However, blood
glucose elevations were not associated with increased mortality
and morbidity over the length of the trial. These findings are
consistent with previously published reports described in the
present article.

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