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Copyright 2007 by Therapeutic Research Center

Pharmacists Letter / Prescribers Letter ~P.O. Box 8190, Stockton, CA 95208 ~Phone: 209-472-2240 ~Fax: 209-472-2249
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Detail-Document #230103
This Detail-Document accompanies the related article published in
PHARMACISTS LETTER / PRESCRIBERS LETTER
J anuary 2007 ~Volume 23 ~Number 230103


Thiazides and Diabetes

Background
Many studies have documented the benefits of
thiazides in the treatment of hypertension. In
addition to lowering blood pressure, thiazides
reduce morbidity and mortality related to
hypertension. In the NIH-sponsored
Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial (ALLHAT),
thiazide-treated patients had less risk of heart
failure than amlodipine-treated patients. They
also fared better than lisinopril-treated patients in
regard to heart failure, stroke, angina, and
coronary revascularization.
1
There has been some criticism of the methods
and findings of ALLHAT. However, experts still
believe the preponderance of evidence supports
thiazides as good first-line antihypertensives.

In
fact, the Seventh Report of the J oint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (J NC-VII)
recommends thiazides, alone or as combination
therapy, for initial treatment for most patients.
This includes patients with diabetes.
2
The
American Diabetes Association recommends
thiazides as an add-on to an ACE inhibitor or
angiotensin receptor blocker (ARB) if
monotherapy fails.
7
And the National Kidney
Foundation states most patients with diabetic
kidney disease should get this combination to
achieve goal blood pressure.
9
In African
Americans, diuretics are more effective
antihypertensives than ACE inhibitors, ARBs,
beta-blockers, or calcium channel blockers.
2

However, some clinicians avoid using thiazides
out of concern for inducing diabetes or worsening
pre-existing diabetes.

Thiazides, Diabetes, and Outcomes
In one cohort study of hypertensive patients,
53.5% of patients who developed diabetes were
taking a thiazide. Only 30% of patients who did
not develop diabetes were taking a thiazide
(p=0.002).
3
Development of diabetes was an
independent risk factor for cardiovascular events.
Although thiazide use was an independent risk
factor for developing diabetes, it was not an
independent risk factor for cardiovascular events.
The study did not report cardiovascular risk
specifically in thiazide patients who developed
diabetes.
In an analysis of the SHEP trial (Systolic
Hypertension in the Elderly Program), patients
with diabetes upon enrollment had increased
cardiovascular mortality and total mortality.
Placebo patients who developed diabetes also had
an increased risk for adverse cardiovascular
outcomes or death. But patients randomized to
chlorthalidone who subsequently developed
diabetes did not have an increased risk of
cardiovascular events.
4
Re-analysis of the ALLHAT data showed that
despite a higher risk for new-onset diabetes with
chlorthalidone, patients on thiazides still did better
than those on an ACE inhibitor or calcium
channel blocker as initial therapy. Patients who
developed diabetes while on chlorthalidone had a
lower risk for heart disease and heart failure than
if taking lisinopril, and a lower risk of death than
if on amlodipine.
5

In patients who are already diabetic, thiazides
can worsen hyperglycemia, but the effect is small
and does not further increase cardiovascular event
risk.
2,6
In ALLHAT, chlorthalidones benefits
held for diabetics as well as for nondiabetics.
6

Commentary
Its well-known that thiazides increase the risk
of new-onset diabetes. However, this is not
proven to increase cardiovascular events. The
benefit from blood pressure reduction may
outweigh any risk associated with diabetes.

Chlorthalidone was the thiazide used in SHEP
and ALLHAT. There is no evidence to suggest
that outcomes would be worse with
hydrochlorothiazide, the thiazide more commonly
used in practice. To minimize hyperglycemia and
hypokalemia, start with hydrochlorothiazide
25 mg daily, or 12.5 mg in the elderly, and dont
exceed 50 mg/day [Evidence level C; expert
opinion].
10

(Detail-Document #230103: Page 2 of 2)
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Promote exercise and weight control to help offset
effects on glycemic control.
6
Low potassium
levels can cause glucose intolerance, so ensure
adequate potassium intake.
6,8

Continue to recommend thiazides as initial
antihypertensive therapy, alone or in combination,
even in patients with diabetes [Evidence level C;
consensus].
2
Most patients will require
combination therapy. For patients with diabetes,
an ACE inhibitor or ARB is recommended to
reduce proteinuria and cardiovascular events.
2,7,9



Users of this document are cautioned to use their own
professional judgment and consult any other necessary
or appropriate sources prior to making clinical
judgments based on the content of this document. Our
editors have researched the information with input
from experts, government agencies, and national
organizations. Information and Internet links in this
article were current as of the date of publication.

Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level Definition
A High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
B Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
C Consensus
Expert opinion
D Anecdotal evidence
In vitro or animal study
Adapted from Siwek J , et al. How to write an evidence-based
clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this Detail-
Document: Melanie Cupp, Pharm.D., BCPS

References
1. Controversy continues over hypertension
treatment. Pharmacists Letter/Prescribers Letter
2003;19:190401.
2. National Heart, Lung, and Blood Institute. Seventh
Report of the J oint National Committee on
Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure (J NC 7).
http://www.nhlbi.nih.gov/guidelines/hypertension/jn
c7full.pdf. (Accessed December 8, 2006).
3. Verdecchia P, Reboldi G, Angeli F, et al. Adverse
prognostic significant of new diabetes in treated
hypertensive subjects. Hypertension 2004;43:963-
69.
4. Kostis J B, Wilson AC, Freudenberger RS, et al.
Long-term effect of diuretic-based therapy on fatal
outcomes in subjects with isolated systolic
hypertension with and without diabetes. Am J
Cardiol 2005;95:29-35.
5. Barzilay J I, Davis BR, Cutler J A, et al. Fasting
glucose levels and incident diabetes mellitus in
older nondiabetic adults randomized to receive 3
different classes of antihypertensive treatment: a
report from the Antihypertensive and Lipid-lowering
Treatment to Prevent Heart Attack Trial (ALLHAT).
Arch Intern Med 2006;166:2191-201.
6. Davis BR, Furberg CD, Wright J T J r, et al.
ALLHAT: setting the record straight. Ann Intern
Med 2004;141:39-46.
7. American Diabetes Association. Standards of
medical care in diabetes. Diabetes Care 2005;28
Suppl 1:S4-S36.
8. Saseen J J , Carter BL. Essential hypertension. In:
Koda-Kimble MA, Young LY, Kradjan WA, et al.,
eds. Applied Therapeutics: the clinical use of
drugs. 8
th
ed. Philadelphia: Lippincott Williams &
Wilkins, 2005.
9. National Kidney Foundation. K/DOQI Clinical
Practice Guidelines on Hypertension and
Antihypertensive Agents in Chronic Kidney
Disease.
http://www.kidney.org/professionals/kdoqi/guideline
s_bp/guide_8.htm. (Accessed November 8, 2006).
10. Carter BL, Ernst ME, Cohen J D.
Hydrochlorothiazide versus chlorthalidone:
evidence supporting their interchangeability.
Hypertension 2004;43:1-6.

Cite this Detail-Document as follows: Thiazides and diabetes. Pharmacists Letter/Prescribers Letter
2007;23(1):230103.


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Copyright 2007 by Therapeutic Research Center