Changes in Serum Potassium Mediate Thiazide-Induced Diabetes
Tariq Shafi, Lawrence J. Appel, Edgar R. Miller III, Michael J. Klag and Rulan S. Parekh
Hypertension. 2008;52:1022-1029; originally published online November 3, 2008;
doi: 10.1161/HYPERTENSIONAHA.108.119438
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Epidemiology/Population Studies
Changes in Serum Potassium Mediate
Thiazide-Induced Diabetes
Tariq Shafi, Lawrence J. Appel, Edgar R. Miller, III, Michael J. Klag, Rulan S. Parekh
Abstract—Thiazides, recommended as first-line antihypertensive therapy, are associated with an increased risk of diabetes.
Thiazides also lower serum potassium. To determine whether thiazide-induced diabetes is mediated by changes in
potassium, we analyzed data from 3790 nondiabetic participants in the Systolic Hypertension in Elderly Program, a
randomized clinical trial of isolated systolic hypertension in individuals aged ⱖ60 years treated with chlorthalidone or
placebo. Incident diabetes was defined by self-report, antidiabetic medication use, fasting glucose ⱖ126 mg/dL, or
random glucose ⱖ200 mg/dL. The mediating variable was change in serum potassium during year 1. Of the 459 incident
cases of diabetes during follow-up, 42% occurred during year 1. In year 1, the unadjusted incidence rates of diabetes
per 100 person-years were 6.1 and 3.0 in the chlorthalidone and placebo groups, respectively. In year 1, the adjusted
diabetes risk (hazard ratio) with chlorthalidone was 2.07 (95% CI: 1.51 to 2.83; P⬍0.001). After adjustment for change
in serum potassium, the risk was significantly reduced (hazard ratio: 1.54; 95% CI: 1.09 to 2.17; P⫽0.01); the extent
of risk attenuation (41%; 95% CI: 34% to 49%) was consistent with a mediating effect. Each 0.5-mEq/L decrease in
serum potassium was independently associated with a 45% higher adjusted diabetes risk (95% CI: 24% to 70%;
P⬍0.001). After year 1, chlorthalidone use was not associated with increased diabetes risk. In conclusion,
thiazide-induced diabetes occurs early after initiating treatment and appears to be mediated by changes in serum
potassium. Potassium supplementation might prevent thiazide-induced diabetes. This hypothesis can and should be
tested in a randomized trial. (Hypertension. 2008;52:1022-1029.)
Key Words: hypertension 䡲 diabetes mellitus 䡲 thiazide diuretics 䡲 chlorthalidone 䡲 hypokalemia 䡲 potassium
H
ypertension affects ⬎65 million US adults1 and ⬇1
billion people worldwide.2 It is the leading risk factor
for coronary heart disease, stroke, and kidney failure. Thiazide diuretics are currently recommended as the first-line
therapy of hypertension.3 Thiazides, however, are associated
with an increased risk of developing diabetes. In the Systolic
Hypertension in the Elderly Program (SHEP), use of the
thiazide diuretic chlorthalidone was associated with a 50%
higher risk of incident diabetes compared with placebo.4
Similarly, in the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT), treatment
with chlorthalidone was associated with a 39% increased risk
of incident diabetes compared with amlodipine and 48%
higher risk compared with lisinopril.5 Continued concern
regarding this increased risk of diabetes is one of the primary
factors limiting the widespread use of thiazide diuretics
despite the national recommendations from the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.6 – 8
Thiazide use increases urinary potassium losses and lowers
the serum potassium level. Because 98% of the total body
potassium is intracellular, and serum potassium concentration
is tightly regulated, frank hypokalemia (a serum potassium
⬍3.5 mEq/L) only occurs in the setting of severe potassium
depletion.9 –11 A few small studies, with ⬍50 participants
observed for 1 to 4 weeks, have evaluated the effect of
experimentally induced hypokalemia on glucose homeostasis.9,10,12–14 In these studies, hypokalemia was associated with
hyperglycemia because of decreased insulin secretion. With
moderate potassium losses, serum potassium can decrease
from baseline but stay above the clinically defined threshold
of hypokalemia. Furthermore, even moderate potassium loss
is associated with adverse outcomes, such as increased blood
pressure (BP), increased salt sensitivity, increased bone
turnover, and stroke.11 It has been hypothesized that thiazideinduced diabetes may result from thiazide-induced changes in
potassium.15
Received July 28, 2008; first decision August 16, 2008; revision accepted October 2, 2008.
From the Department of Medicine, Division of Nephrology (T.S., R.S.P.), and General Internal Medicine (L.J.A., E.R.M., M.J.K.), Department of
Pediatrics, Division of Nephrology (R.S.P.), Johns Hopkins University School of Medicine; Department of Epidemiology (L.J.A., E.R.M., M.J.K.,
R.S.P.), Johns Hopkins Bloomberg School of Public Health; and the Welch Center for Prevention, Epidemiology and Clinical Research (L.J.A., E.R.M.,
M.J.K., R.S.P.), Baltimore, Md.
Parts of this work were presented in abstract form at the 40th Annual Meeting of the American Society of Nephrology, November 2–5, 2007, San
Francisco, Calif.
Correspondence to Tariq Shafi, Division of Nephrology, Johns Hopkins University School of Medicine, 4940 Eastern Ave, B2/Room 209, Baltimore,
MD 21224-2780. E-mail tshafi@jhmi.edu
© 2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.108.119438
1022
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Shafi et al
The objective of this study was to determine whether
thiazide-induced changes in serum potassium mediate the
effect of thiazide diuretics on incident diabetes in hypertensive individuals participating in a large, randomized trial.
Methods
Design and Participants
The protocol for this analysis of the SHEP deidentified data set16 was
approved by the Johns Hopkins Medicine Institutional Review
Board. Rationale and design of the SHEP trial have been described
previously.17,18 Briefly, SHEP was a randomized, multicenter,
double-masked, placebo-controlled trial conducted at communitybased clinics with recruitment from 1985 to 1988 and follow-up
ending in 1991. The primary aim of the SHEP trial was to determine
whether antihypertensive treatment reduced the risk of stroke in
individuals aged ⱖ60 years with isolated systolic hypertension
defined as systolic BP ⬎160 mm Hg and diastolic BP ⬍90 mm Hg.
The present analysis includes 3790 (80%) of the 4736 SHEP
participants. Participants were excluded if they had baseline diabetes
(n⫽686 [14.5%]), no follow-up glucose (n⫽164 [3.5%]), or no
follow-up serum potassium (n⫽96 [2%]). Baseline diabetes mellitus
was defined by self-report, treatment with antidiabetic agents, fasting
glucose ⱖ126 mg/dL, or random glucose ⱖ200 mg/dL.
Interventions
The participants were randomly assigned to active therapy or
matched placebo. Systolic BP goal was defined as a reduction of
20 mm Hg if systolic BP was between 160 and 179 mm Hg and
reduction to systolic BP ⬍160 mm Hg for those with higher BP.
Participants were started on either chlorthalidone 12.5 mg daily or
matched placebo. Drug dosage (or matched placebo) was doubled if
the BP remained above goal at 8 weeks. If the BP remained above
goal at 16 weeks despite the doubling of dose, atenolol or reserpine
(or matched placebo) was added to the regimen.
Pertinent Laboratory Measurements
Serum potassium was measured at baseline, within a month of
initiating and/or increasing the dose of chlorthalidone (or matched
placebo) and then annually. Serum potassium was also measured
again in follow-up of abnormal values. Potassium supplementation
was prescribed if serum potassium was ⬍3.5 mEq/L at 2 consecutive
visits. Fasting blood samples were obtained at baseline and then at
first, third, and final annual visits but were not required for study
participation. Fasting glucose was measured in 2273 participants
(60%) at baseline. Among 1517 participants without fasting glucose
measurement, random glucose was available for 1374 (91%).
Exposure, Outcome, and Mediating Variables
The primary exposure for this analysis was treatment with chlorthalidone. The primary outcome was incident diabetes defined by
self-report, treatment with antidiabetic agents, fasting glucose ⱖ126
mg/dL, random glucose ⱖ200 mg/dL, or diabetes noted on hospitalization records. The mediating variable was change in serum
potassium defined as baseline potassium minus mean potassium
during year 1. Mean potassium was determined for each individual
by averaging all of the available potassium levels for the individual
during year 1 after randomization. We defined our mediating
variable as the change in serum potassium during year 1, because we
expected most decline in serum potassium to occur early after
initiating chlorthalidone. Change in potassium during year 1 was
adjusted for baseline potassium to reduce the effect of regression to
the mean.19 Sensitivity analyses were conducted in which the
mediating variable, mean potassium in year 1, was replaced with
either the highest potassium in year 1 or serum potassium as a
time-dependant covariate.
Thiazide-Induced Diabetes
1023
Other Covariates
Other covariates in the model included baseline values for the
following: age, gender, race (nonwhite versus white), body mass
index (BMI, weight [kilograms]/height2 [meters]), systolic and diastolic BPs, serum creatinine, fasting serum glucose, and serum
potassium. Missing data for baseline variables were as follows: BMI
1.3%, diastolic BP 0.2%, serum glucose 3.6%, serum potassium
4.8%, and serum creatinine 5.0%. Baseline potassium was more
likely to be missing from the placebo group than from the chlorthalidone group (5.6% versus 4.0%; P⫽0.02). There were no other
differences in missing variables between the 2 groups.
Analytic Methods
Continuous variables were compared using t tests for parametric data
and rank-sum test or robust regression for nonparametric data.
Categorical variables were compared using the 2 test. Missing
baseline data values were imputed with 10 data replicates using ice
and micombine programs in Stata (Stata Corp).20 –22 Participants free
of diabetes were censored at death, at the end of the trial, or at the last
annual visit date for those lost to follow-up. Cumulative incidence of
diabetes was assessed using the nonparametric Kaplan-Meier product-limit estimator. Incidence rates (IR) of diabetes were calculated
using the person-time approach. Linear association between the
independent continuous variables and diabetes was assessed visually
using lowess smoothed log-odds plots. In the final model, BMI was
analyzed as a linear spline with a knot at 20 kg/m2 and fasting
glucose as a linear spline with a knot at 100 mg/dL. The association
between change in serum potassium and diabetes was linear based on
visual inspection of smoothed log-odds plots, and there was no
improvement in model fit using splines based on quartiles and
clinical cutoffs. Cox proportional hazards regression with treatmenttime interaction was used to model the adjusted risk of diabetes with
chlorthalidone compared to placebo.23 Proportional hazards assumptions were assessed graphically and by hypothesis-based tests.23
Number needed to harm24 was calculated as recommended for
survival analysis.25 The mediating variable was defined as a predictor hypothesized to lie on the causal pathway between exposure and
outcome. Mediation was assessed in the following 5 steps26: (1)
determine whether the exposure (chlorthalidone) predicts the mediator (change in serum potassium); (2) determine whether the mediator (change in serum potassium) independently predicts the outcome (diabetes); (3) determine the adjusted hazard ratio (HR) of
diabetes from chlorthalidone without including change in potassium
in the regression model (this HR represents the “total effect” of
chlorthalidone); (4) determine the adjusted HR of diabetes from
chlorthalidone with change in potassium in the regression model
(this HR represents the “direct effect” of chlorthalidone without the
effect mediated by changes in potassium); (5) calculate mediation,
which represents the change in the coefficient (log HR) of chlorthalidone after adjustment for change in potassium. Mediation was
calculated as follows: (coefficient for total effect⫺coefficient for
direct effect)/coefficient for total effect⫻100. Mediation was considered significant if the log HR was attenuated by ⬎15%. A
bias-corrected 95% CI for mediation was calculated using bootstrapping with replacement (1000 samples).26
The probability of incident diabetes in year 1 by treatment
assignment and change in potassium was predicted using the
adjusted Cox regression model. A number of different sensitivity
analyses were conducted to determine the robustness of our results.
The risk of incident diabetes with different doses of chlorthalidone,
as well as with the combination of chlorthalidone and atenolol, was
determined. The effect of potassium supplementation on incident
diabetes mellitus was also assessed. Data were analyzed using Stata
9.2. Statistical significance was defined as P⬍0.05 using 2-tailed
tests.
Results
The baseline characteristics of 3790 participants are presented in Table 1. There were no significant differences between
the 2 randomized groups. There were 459 incident cases of
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1024
Hypertension
December 2008
Table 1. Baseline Characteristics of the 3790 Nondiabetic
Participants From the SHEP Trial
Subjects randomly assigned
Placebo
Chlorthalidone
1862 (49.1)
1928 (50.9)
72 (6.6)
72.3 (6.7)
Age, y
Gender
Men
Women
791 (42.5)
812 (42.1)
1071 (57.5)
1116 (57.9)
Race/ethnicity
White
1516 (81.4)
1550 (80.4)
346 (18.6)
378 (19.6)
Nonwhite
Baseline systolic BP, mm Hg
169.9 (9.2)
170.4 (9.5)
Baseline diastolic BP, mm Hg
76.6 (9.6)
76.7 (9.9)
27.3 (5.0)
27.4 (4.9)
No. available (%)
1102 (59.2)
1171 (60.7)
Mean
98.8 (10.3)
98.9 (10.8)
69.1 (16.0)
68.9 (16.6)
4.5 (0.5)
4.5 (0.5)
2
Baseline BMI, kg/m
Baseline fasting glucose, mg/dL
Estimated GFR, mL/min per 1.73 m2
Baseline potassium, mEq/L
Data are N (%) or mean (SD). GFR indicates glomular filtration rate. GFR
(mL/min/1.73 m2)⫽186⫻(Serum Creatinine)⫺1.154⫻(age)⫺0.203⫻(0.742 if
female)⫻(1.210 if African American).
Cumulative Proportion (%)
diabetes during 15 830 person-years of follow-up. Of the 459
cases, 266 were in the chlorthalidone group and 193 in the
placebo group. The median follow-up time was 4.4 years
(interquartile range: 3.5 to 5.1 years). The higher unadjusted
cumulative incidence of diabetes in the chlorthalidone group
(Figure 1) was apparent at year 1, when first annual fasting
glucose measurements were performed. Of the 459 incident
cases of diabetes, 191 (41.6%) occurred during the first year
(chlorthalidone, n⫽129; placebo, n⫽62). During year 1, the
unadjusted IR of diabetes per 100 person-years in the
chlorthalidone group was 6.1 and was significantly higher
than the placebo group (IR: 3.0; P for IR ratio⬍0.001). After
year 1, there was no significant difference in the unadjusted
IR of diabetes mellitus between the 2 groups (chlorthalidone:
2.4; placebo: 2.3; P for IR ratio⫽0.7).
30%
Placebo
Chlorthalidone
10%
0
0
Number at
Risk
Chlorthalidone 1,928
Placebo 1,862
1
2
4
3
Time Since Randomization (Years)
1,797
1,799
1,739
1,748
Placebo
Chlorthalidone
8
6
4
2
0
< 0.5 mEq/L Decrease
≥0.5 mEq/L Decrease
Change in Serum Potassium from Baseline
No. of Cases
No. of Participants
52
1,579
53
1,075
6
179
67
776
Figure 2. Unadjusted incidence rates of diabetes in year 1 by
change in serum potassium in the 3790 nondiabetic participants
from the SHEP trial.
Assessment of Change in Serum Potassium as a
Mediating Variable
Step 1: Chlorthalidone-Induced Change in
Serum Potassium
Chlorthalidone use was associated with lowering of serum
potassium. During year 1, the average serum potassium (SD)
was significantly lower in the chlorthalidone group (4.1 [0.4]
mEq/L) than in placebo group (4.5 [0.3] mEq/L; P⬍0.001).
This change represented a decrease of 0.4 (0.4) mEq/L from
baseline in the chlorthalidone group during year 1 (P⬍0.001).
There was no change in serum potassium in the placebo
group.
Step 2: Changes in Serum Potassium and Diabetes
During year 1, greater decrease in serum potassium was
associated with a higher unadjusted IR of diabetes (Figure 2).
In the fully adjusted Cox proportional hazards model, each
0.5-mEq/L decrease in serum potassium from the average
baseline level was associated with a 45% higher risk of
incident diabetes (95% CI: 24% to 70% higher risk;
P⬍0.001) throughout the study period. The highest risk was
observed in individuals with a ⬎0.5-mEq/L decrease in
serum potassium (Table 2).
Step 3: Chlorthalidone-Induced Diabetes (Total Effect
of Chlorthalidone)
In a Cox proportional hazards model, adjusted for age,
gender, race, BMI, systolic and diastolic BP, serum creatinine, and fasting glucose (Table 3), the risk of diabetes from
chlorthalidone during year 1 was 2 times higher than placebo
(HR: 2.07; 95% CI: 1.51 to 2.83; P⬍0.001). The number
needed to harm was 29 (95% CI: 17 to 60). After year 1,
chlorthalidone was not associated with increased diabetes risk
(HR: 1.08; 95% CI: 0.84 to 1.39; P⫽0.6).
Log-rank p = 0.0008
20%
Incidence Rate
(per 100 person-yrs)
Characteristics
10
5
1,632
1,075
462
1,648
1,080
446
Figure 1. Unadjusted cumulative incidence of diabetes in the
3790 nondiabetic participants from the SHEP trial.
Step 4: Chlorthalidone-Induced Diabetes
(Direct Effect of Chlorthalidone)
The Cox model for the total effect of chlorthalidone (step 3)
was further adjusted for change in serum potassium. The HR
for the direct effect of chlorthalidone in this model was 1.54
(95% CI: 1.09 to 2.17; number needed to harm: 57; 95% CI:
27 to 329; P⫽0.01).
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Shafi et al
Table 2. Change in Serum Potassium and Risk of Incident
Diabetes in the 3790 Nondiabetic Participants From the SHEP
Trial
Models
Change in Potassium
No.
Hazard Ratio (95% CI)
P
Model 1
Continuous
(per 0.5 mEq/L
decrease)
3790
1.45 (1.24 to 1.70)
⬍0.001
Model 2
40.7%; 95% CI: 34.3% to 49.3%). This change exceeds the
⬎15% attenuation criterion for mediation (Table 3).
Figure 3 graphically depicts the risk of developing
diabetes based on assignment to chlorthalidone or placebo
and the occurrence of 0.5-mEq/L decline in serum potassium. Treatment with chlorthalidone and/or lowering of
serum potassium was associated with a higher probability
of developing diabetes mellitus compared with assignment
to placebo and no decrease in potassium from baseline.
Quartile 1: ⱕ⫺0.1*
806
Reference
Quartile 2: ⫺0.1 to 0.2*
995
1.19 (0.87 to 1.62)
0.26
Quartile 3: 0.2 to 0.5
950
1.39 (0.99 to 1.94)
0.06
Sensitivity Analyses
⬎0.5
858
1.99 (1.35 to 2.94)
0.001
With restricting the analysis to participants with fasting
serum glucose available at baseline and year 1 or changing
the definition of incident diabetes (self-reported diagnosis,
use of antidiabetic medications, or fasting serum glucose
ⱖ140 mg/dL), the magnitude and direction of mediation
were unchanged (Table 3). A 6-month lag analysis and
analysis restricted to participants with baseline fasting
glucose ⬍100 mg/dL and random glucose ⬍125 mg/dL
also showed similar results, suggesting that the observed
high early risk of diabetes mellitus was not because of
preclinical disease. Similar results were obtained when the
definition of the mediating variable (change in serum
potassium) was modified. Analyses performed without
P trend
⬍0.001
Change in potassium indicates baseline potassium⫺mean potassium during
year 1 (in mEq/L). Cox regression adjusted for treatment assignment, age,
gender, race, BMI, systolic and diastolic BP, baseline serum creatinine, and
baseline fasting serum glucose.
*Minus sign and values ⬍0 indicate that mean potassium in year 1 was
higher than baseline potassium.
Step 5: Calculating Mediation
In the direct model for chlorthalidone-induced diabetes
(step 4), there was a marked attenuation in the coefficient
(log HR) of diabetes from chlorthalidone (mediation:
Table 3.
1025
Thiazide-Induced Diabetes
Sensitivity Analyses for the Risk of Diabetes in Year 1 in the 3790 Nondiabetic Participants From the SHEP Trial
Total Effect
Direct Effect
(Not Adjusted for Change in Potassium) (Adjusted for Change in Potassium)
No. of
Participants
HR (95 % Cl)
P
HR (95 % Cl)
3790
2.07 (1.50 to 2.83)
⬍0.001
1.54 (1.09 to 2.17)
1736
2.05 (1.36 to 3.10)
0.001
3888
1.22 (0.83 to 1.80)
Six-month lag analysis㛳
3786
Random glucose ⱕ125 and fasting
glucose ⬍100¶
Models for Diabetes Risk*
Mediation
%
(95 % Cl)†
0.01
40.7
(34.3 to 49.3)
1.63 (1.05 to 2.52)
0.03
32.0
(24.2 to 41.4)
0.32
0.88 (0.58 to 1.34)
0.56
164.3
(99.6 to 418.3)
2.09 (1.53 to 2.85)
⬍0.001
1.57 (1.11 to 2.20)
0.01
38.8
(32.9 to 47.1)
2502
1.77 (1.07 to 2.92)
0.03
1.22 (0.71 to 2.09)
0.47
65.2
(50.0 to 91.3)
Highest potassium in year 1
3790
2.07 (1.51 to 2.83)
⬍0.001
1.49 (1.07 to 2.08)
0.02
45.1
(39.2 to 53.5)
Time-varying potassium#
3790
1.71 (1.32 to 2.22)
⬍0.001
1.49 (1.13 to 1.96)
⬍0.01
25.7
(10.4 to 47.1)
Without data imputation**
2241
2.39 (1.59 to 3.58)
⬍0.001
1.88 (1.22 to 2.91)
⬍0.01
27.5
(10.5 to 58.7)
Adjustment for BP at year 1 Annual visit††
3790
2.04 (1.45 to 2.87)
⬍0.001
1.52 (1.07 to 2.19)
0.02
41.3
(34.4 to 51.1)
P
Primary analysis
Main model for the risk of diabetes*
Sensitivity analysis
Available fasting glucose‡
Fasting glucose at baseline and year 1
Changing diabetes definition§
History/medications⫹fasting glucose
ⱖ140
Evaluating pre-existing disease
Different potassium measures
Change in potassium⫽baseline serum potassium⫺mean serum potassium during year 1 (in milliequivalents per liter). All of the glucose values refer to baseline
serum glucose in milligrams per deciliter.
*Cox regression adjusted for age, gender, race, BMI, systolic and diastolic BP, baseline serum creatinine, and baseline fasting serum glucose.
†Mediation was calculated as follows: (log HR without adjustment⫺log HR with adjustment)/log HR without adjustment⫻100.
‡Analysis was restricted to individuals with available fasting glucose at baseline and year 1 annual visit.
§Baseline and incident diabetes were defined as follows: self-reported diagnosis of diabetes, antidiabetic medication use, or fasting glucose ⱖ140 mg/dL.28
㛳Data analyzed after excluding time and events for the first 6 months.
¶Analysis was restricted to those with random glucose ⱕ125 mg/dL and fasting glucose ⬍100 mg/dL.
#Robust variance estimate.
**Decrease in the number of participants reflects software-based model-wise deletion in regression.
††Model adjusted for baseline and year 1 systolic and diastolic BPs.
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1026
Hypertension
Probability of Diabetes (%)
25
December 2008
Chlorthalidone + Serum Potassium Decrease = 0.5 mEq/L
Chlorthalidone (No Potassium Changes)
Placebo + Serum Potassium Decrease = 0.5 mEq/L
Placebo (No Potassium Changes)
20
15
Table 4. Factors Associated With Diabetes Risk in Year 1 in
the 3790 Nondiabetic Participants From the SHEP Trial
Models for Diabetes Risk*
HR (95% Cl)
P
Model 1: baseline characteristics
10
5
Available
Baseline
Potassium
Levels*
0
3.0
3.5
4.0
4.5
5.0
Serum Potassium (mEq/L)
5.5
6.0
Figure 3. Predicted probability of developing diabetes in year 1
by chlorthalidone use and change in serum potassium in the
3790 nondiabetic participants from the SHEP trial. Predicted
from Cox proportional hazards regression adjusted for age, gender, race, baseline systolic and diastolic BP, baseline BMI,
baseline creatinine, baseline fasting glucose, and change in
serum potassium. Change is serum potassium⫽baseline serum
potassium ⫺ mean serum potassium in year 1. *Each dot near
the abscissa indicates a data point.
data imputation and analyses adjusting for attained BP at
year 1 also yielded results similar to primary analysis.
Other Risk Factors for Diabetes
Nonwhite race, higher BMI, and fasting serum glucose
were all independently associated with a higher risk of
diabetes in year 1 (Table 4). The HR per 10-mg/dL
increase in fasting glucose was 1.87 among those with
baseline fasting glucose ⬍100 mg/dL and 3.23 among
those with a baseline level ⱖ100 mg/dL. At the time of the
first annual visit, in the active therapy group 65% of the
participants were taking chlorthalidone ⱕ12.5 mg/d, 23%
were taking chlorthalidone 25 mg/d, and 12% were taking
atenolol in addition to chlorthalidone. Higher doses of
chlorthalidone and the use of atenolol were associated with
a higher risk of diabetes in year 1. In “on-treatment
analyses,” the risk of diabetes was similar to the main
analysis in those deemed compliant based on urinary
chlorthalidone assays. Hypokalemia (serum potassium
ⱕ3.5 mEq/L) was noted during year 1 in 444 participants
(23%) in the chlorthalidone group and 58 participants
(3.1%) in the placebo group. Potassium supplement use in
year 1, however, was recorded for only 7.1% and 2.9% of
the participants in the chlorthalidone and placebo groups,
respectively, and the mean (SD) potassium dose was 24
(12) mEq/d. These data suggest potassium supplement use,
both frequency and amount, were incompletely reported.
Adjustment for potassium supplement use in year 1 did not
attenuate the risk of diabetes associated with change in
serum potassium or chlorthalidone use. Serum potassium
levels after supplementation were not available in the
database.
Discussion
In our analyses of the hypertensive, nondiabetic participants
in the SHEP trial, 2 principal findings emerged. First,
Race (Nonwhite vs white)
1.32 (1.06 to 1.64)
0.01
BMI (per 5 kg/m2)†
1.23 (1.12 to 1.34)
⬍0.001
Fasting glucose (per 10 mg/dL)
Fasting glucose ⬍100 mg/dL
1.87 (0.99 to 3.55)
0.05
Fasting glucose ⱖ100 mg/dL
3.23 (2.48 to 4.20)
⬍0.001
Chlorthalidone (ⱕ12.5 mg)
vs placebo
1.70 (1.19 to 2.43)
0.003
Chlorthalidone (25 mg) vs
placebo
2.37 (1.55 to 3.65)
⬍0.001
Chlorthalidone (25 mg)⫹
atenolol vs placebo‡
3.16 (1.90 to 5.26)
⬍0.001
Models 2 to 4: postrandomization
characteristics
Model 2: medication doses
P trend
⬍0.001§
Model 3: potassium
supplement use㛳
Supplement use vs no use¶
0.89 (0.47 to 1.68)
0.7
2.30 (1.5 to 3.51)
⬍0.001
Model 4: On treatment
analysis#
Chlorthalidone vs placebo
*Cox regression adjusted for treatment assignment, age, gender, race, BMI,
systolic and diastolic BP, baseline serum creatinine, and baseline fasting serum
glucose.
†Above 20 kg/m2.
§P value for interaction between chlorthalidone and atenolol⫽0.93.
‡Because of study design (stepped care), atenolol was added if BP was not
at goal with chlorthalidone at 25 mg/d.
㛳Data show any reported potassium supplement use during year 1.
¶P value for interaction between potassium supplement use and change in
potassium⫽0.5.
#Data are for on-treatment analysis excluding drop-ins (placebo-assigned
participants with positive urinary chlorthalidone assay) and drop-outs
(chlorthalidone-assigned participants with negative urinary chlorthalidone
assay).
thiazide-induced diabetes occurred early after initiating therapy. The 2-fold higher risk of diabetes from chlorthalidone
was confined to the first year of the study. After year 1,
chlorthalidone use was not associated with increased risk of
diabetes. Second, this chlorthalidone-induced diabetes appeared to be mediated by changes in serum potassium. Each
0.5-mEq/L decrease in serum potassium from the baseline
during year 1 was associated with a 45% higher risk of
diabetes, independent of treatment assignment, and this effect
persisted throughout the study period.
Total body potassium depletion is difficult to assess clinically. Decline in serum potassium without frank hypokalemia is generally associated with moderate lowering of total
body potassium.11 A 0.5-mEq/L decrease in serum potassium
below 4 mEq/L represents an ⬇5% or 150- to 200-mEq
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Shafi et al
decrease in total body potassium.27 In our analysis, greater
decrease in serum potassium from baseline was associated
with a higher risk of diabetes. If potassium depletion is
underestimated by serum potassium, then our finding of 41%
mediation may be an underestimation, and the actual degree
of mediation may be much higher. We could not detect a
beneficial effect of potassium supplementation on diabetes in
our analysis. A likely reason for this finding is incomplete
recording of potassium supplement use. Other possible reasons include a low threshold for initiating supplementation
(serum potassium ⬍3.5 mEq/L on 2 occasions) and inadequate repletion.11
The association between thiazide diuretics and diabetes has
been known for ⬇50 years.4,13,28 –30 In small clinical experiments, potassium depletion induced with9,13,14 or without
diuretics10,12 was associated with glucose intolerance, which
reversed with potassium supplementation. Glucose intolerance, however, did not improve in a trial of potassium
supplementation in 16 patients with 6 weeks of follow-up31
and another trial using potassium-sparing diuretics in 202
patients followed for 8 weeks.32 A quantitative review analyzing 59 trials with thiazide diuretic arms reported a significant negative correlation between the change in mean serum
potassium and the change in mean serum glucose. This
analysis, however, combined results of fasting and random
glucose levels across studies that included diabetic and
nondiabetic participants.33 In addition, the dose of thiazide
diuretics varied widely: 12.5 to 100.0 mg/d for chlorthalidone
and 12.5 to 400.0 mg/d for hydrochlorothiazide. In a recent
analysis of the 9802 nondiabetic participants of ALLHAT,
the adjusted odds for incident diabetes at year 2 in the
chlorthalidone group were 38% higher compared with the
amlodipine group and 82% higher compared with the lisinopril group.5 Similar to our study, the odds of chlorthalidoneinduced diabetes in the subsequent years were not significantly higher. Although this ALLHAT analysis addressed
potassium depletion (serum potassium ⬍3.2 mEq/L), it did
not specifically address mediation.
A previous analysis of SHEP, using a 140-mg/dL cutoff for
fasting glucose to diagnose diabetes, had noted an increased
incidence of diabetes with chlorthalidone, but the results were
not statistically significant.28 Our analysis, using the currently
accepted cutoff for fasting glucose (ⱖ126 mg/dL), resulted in
a higher number of incident diabetes cases in year 1 (n⫽191)
as compared with the original report from SHEP (n⫽120).
Sensitivity analysis using the older definition (Table 3)
resulted in a statistically nonsignificant HR for diabetes in
year 1, but the direction of mediation by change in serum
potassium was similar to the primary analysis.
The cardiovascular risk associated with thiazide-induced
diabetes continues to be a subject of ongoing debate. Some
have suggested that this diabetes is different from “naturally occurring” diabetes, whereas others have argued that
this “new-onset diabetes” is not benign.6,8,15,34,35 The
increased risk of diabetes with chlorthalidone during year
1 noted in our study was based mostly on detecting
changes in fasting serum glucose. This initial increased
risk, followed by no risk of diabetes for the remainder of
Thiazide-Induced Diabetes
1027
the trial duration, suggests a potential biochemical “unmasking” of diabetes in those individuals at higher risk of
diabetes at baseline.
Pancreatic release of insulin is controlled via ATPsensitive potassium channels and L-type calcium channels on
the -cell surface.36 Increase in plasma glucose closes the
potassium channels and increases insulin secretion. Changes
in serum potassium may prevent closure of these channels,
and this may be the mechanism behind the decrease in insulin
secretion noted in some studies.12,14,37 Hypertension is often
associated with insulin resistance.38 In the presence of insulin
resistance, pancreatic -cells increase insulin production,
maintaining euglycemia.39 A decrease in -cell insulin release because of changes in potassium may lead to hyperglycemia in individuals with insulin resistance. Thiazides may
also have effects on glucose homeostasis independent of
those mediated via potassium. In animal models, thiazides
can reduce glucose-mediated calcium entry into the -cells
decreasing insulin secretion,40 and in high doses, such as
hydrochlorothiazide 10 mg/kg per day, can increase insulin
resistance.41 Thiazides also cause magnesium depletion.
Magnesium depletion has been associated with diabetes
mellitus in several cohort studies,42– 44 and magnesium supplementation in diabetics is associated with a decrease in
fasting glucose levels.45 Whether magnesium depletion also
mediates thiazide-associated diabetes is unknown.
The strength of our study includes its nondiabetic population at baseline, large sample size and long duration of
follow-up, as well as the large number of events providing
adequate statistical power to detect differences between the 2
groups. The comparison of chlorthalidone with placebo is
also advantageous, because medications such as angiotensinconverting enzyme inhibitors and angiotensin receptor blockers may reduce the risk of diabetes, as well as increase serum
potassium. Finally, although false-positive results because of
multiple testing are always a possibility in any analysis, our
study was based on an a priori hypothesis, biological plausibility, and evidence from previous association studies. Limitation of our study includes the potential for uncontrolled
confounding, because diet, physical activity, and magnesium
were not measured. As discussed above, there may also be
residual confounding, because serum potassium may underestimate total body potassium depletion. There was also
limited information available regarding potassium supplementation and changes in serum potassium after supplementation. Finally, there is the possibility, albeit unlikely, that
some variable that is highly correlated with serum potassium
levels is the mediating variable rather than serum potassium.
Our study has important implications for the clinical
practitioner and for future research. For the practitioner, our
study provides reassurance that diabetes occurring after ⬎1
year of thiazide therapy is unlikely to be thiazide induced. In
addition, nondiabetic patients currently on thiazide therapy
for ⬎1 year are unlikely to develop thiazide-induced diabetes.
For future research, our study suggests that trials of potassium
supplementation to prevent diabetes may not need to last for
⬎1 year to observe a difference in outcomes.
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1028
Hypertension
December 2008
Perspectives
Thiazide-induced diabetes in hypertensive individuals occurs
early after initiating therapy and appears to be mediated by
thiazide-induced changes in potassium. Individuals with fasting glucose ⱖ100 mg/dL, treatment with chlorthalidone
doses ⬎12.5 mg/d, and a decrease in potassium from baseline
ⱖ0.5 mEq/L are at the highest risk of developing diabetes.
Routine supplementation with potassium is a plausible treatment to prevent thiazide-induced diabetes. This hypothesis
can and should be tested in randomized, controlled trials.
Acknowledgments
The SHEP is conducted and supported by the National Heart, Lung,
and Blood Institute in collaboration with the SHEP Investigators.
This article was prepared using a limited access data set obtained by
the National Heart, Lung, and Blood Institute and does not necessarily reflect the opinions or views of the SHEP or the National
Heart, Lung, and Blood Institute.
Sources of Funding
T.S. was supported by a Renal Disease Training Grant
(5T32DK007732-12) from the National Institutes of Health/National
Institute of Diabetes and Digestive and Kidney Diseases.
Disclosures
None.
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Correction
In the Hypertension article by Shafi et al (Shafi T, Appel LJ, Miller ER, III, Klag MJ, Parekh RS.
Changes in serum potassium mediate thiazide-induced diabetes. Hypertension. 2008;52:1022–
1029.), there is text missing in Table 2. The correct table appears below.
The authors regret the error.
Table 2. Change in Serum Potassium and Risk of Incident Diabetes Mellitus in the 3790
Nondiabetic Participants From the SHEP Trial
Models
Change in Potassium
No.
Hazard Ratio (95% CI)
P
Model 1
Continuous (per 0.5 mEq/L decrease)
3790
1.45 (1.24 to 1.70)
⬍0.001
Model 2
Quartile 1: ⱕ⫺0.1*
806
Reference
Quartile 2: ⫺0.1 to 0.2*
995
1.19 (0.87 to 1.62)
0.26
Quartile 3: 0.2 to 0.5
950
1.39 (0.99 to 1.94)
0.06
Quartile 4: ⬎0.5
858
1.99 (1.35 to 2.94)
0.001
P trend⬍0.001
Change in potassium indicates baseline potassium⫺mean potassium during year 1 (in mEq/L). Cox regression was
adjusted for treatment assignment, age, gender, race, BMI, systolic and diastolic BP, baseline serum creatinine, and
baseline fasting serum glucose.
*Minus sign and values ⬍0 indicate that mean potassium in year 1 was higher than baseline potassium.
(Hypertension. 2009;53:e19.)
© 2009 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.109.000254
e19