Abdominal Obesity Is Associated With Potassium Depletion and Changes in Glucose Homeostasis During Diuretic Therapy

Abstract

The activation of the renin‐angiotensin system (RAS) is an important mechanism that contributes to hypertension in obese individuals. Thiazide diuretics also activate the RAS in response to volume contraction and can lead to a decrease in serum potassium values and glucose metabolism abnormalities. To evaluate the impact of abdominal obesity on potassium depletion and glucose homeostasis in hypertensive patients receiving thiazide therapy, the authors studied 329 hypertensive patients without known diabetes or impaired renal function. Patients were stratified into 2 major groups according to whether they used thiazide diuretic therapy, and each group was further divided in 2 subgroups according to the presence of abdominal obesity. The authors demonstrated that obese patients receiving diuretic therapy had lower plasma potassium levels and higher glucose values compared with nonobese patients receiving diuretic therapy. In conclusion, abdominal obesity predisposes to potassium depletion during diuretic therapy in association with effects on glucose homeostasis.

Abdominal obesity and arterial hypertension are major components of the metabolic syndrome. ¹ Arterial hypertension was described as the most frequent diagnostic criterion of metabolic syndrome in both sexes in an apparently healthy Japanese population. ² The association between obesity, especially abdominal obesity, and hypertension has been demonstrated by several studies. ³ , ⁴ Abdominal obesity is clinically measured by waist circumference, ⁵ which has been referred to as a hypertriglyceridemic waist due to its ability, in association with fasting triglyceride levels, to identify individuals at increased risk for coronary heart disease. ⁶ In addition, this pattern of fatty distribution has been described as an independent risk factor for arterial hypertension ⁷ and type 2 diabetes ⁸ and has been associated with the metabolic syndrome in individuals with normal body weight. ⁹

Several mechanisms have been proposed to explain the development of hypertension in obesity. ¹⁰ In particular, the activation of the systemic and adipose renin‐angiotensin system (RAS) has been described as a potentially important mechanism, ¹¹ , ¹² even in the presence of sodium retention and volume expansion consequent to enhanced sympathetic activity. ¹³ , ¹⁴ Increased levels of circulating components of the RAS have been observed in obese individuals, showing a significant decrease after weight loss. ¹² In addition, a functional RAS located in adipose tissue with expression of many of RAS components has been demonstrated. ¹¹ , ¹⁵ , ¹⁶ , ¹⁷ Furthermore, Paula and colleagues ¹⁸ demonstrated that aldosterone has an important role in hypertension‐related obesity and that aldosterone antagonism was effective in reducing blood pressure in dogs with obesity‐induced hypertension.

Essential hypertension is an insulin‐resistant state per se, even in the absence of obesity or other metabolic abnormalities. ¹⁹ This may explain the higher prevalence of glucose intolerance in patients with untreated hypertension, ²⁰ particularly in persons receiving antihypertensive therapy. ²¹ In addition, the association of obesity and hypertension seems to be additive, leading to a higher insulin resistance state and hyperinsulinemia. ²¹

It is well established that high doses of thiazide diuretics can lead to a decrease in serum potassium levels ²² and glucose metabolism abnormalities with an increased risk of diabetes, compared with some of the other antihypertensive agents. ²³ , ²⁴ Potassium depletion is attributed to the activation of the RAS in response to volume contraction, enhanced potassium exchange with sodium in the distal tubule, and potassium entering the cells due to diuretic‐induced alkalosis. ²² Potassium depletion, ²⁵ , ²⁶ even to a limited degree, ²⁷ , ²⁸ has been associated with glucose intolerance. The proposed mechanisms responsible for this association are reduced insulin release ²⁶ , ²⁸ and peripheral insulin resistance. ²⁹ Among the mechanisms of impaired insulin secretion are the reduced β‐cell responsiveness to glucose stimulus, ²⁶ , ²⁸ a high proportion of proinsulin in circulation, ²⁹ an abnormal initial insulin release phase, ³⁰ and the opening of calcium‐activated potassium channels. ³¹ The reduction in insulin‐mediated glucose disposal was described previously, ²⁹ but there are controversies. ²⁸ Rowe and associates ²⁸ have described only impaired insulin secretion, not abnormal peripheral tissue sensitivity, with diet‐induced potassium depletion. In addition, the mechanism underlying the decrease of insulin‐mediated glucose disposal is still unclear.

Considering that obese hypertensive patients are insulin‐resistant and prone to glucose intolerance and RAS activation, the aim of our study was to evaluate whether the presence of abdominal obesity was associated with lower plasma potassium levels and higher plasma glucose levels in hypertensive patients on thiazide therapy. A secondary objective was to quantify the impact of central obesity on cardiovascular risk in this population of hypertensive patients.

METHODS

A cross‐sectional study analyzed 329 hypertensive patients followed in our institution between May 2005 and May 2006. The protocol was approved by the institutional ethics committee and all participants provided written informed consent.

Exclusion criteria included a previous diagnosis of diabetes; dyslipidemia therapy; corticosteroid, aldosterone‐blocking agent, or generic potassium supplement use; and serum creatinine level >1.2 mg/dL or a creatinine clearance <50 mL/min. Diabetes was defined as a fasting plasma glucose level ≥126 mg/dL and/or 2‐hour postload glucose level ≥200 mg/dL, ³² self‐reported history of diabetes, or use of antidiabetic medication.

Hypertension was defined as a systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg ³³ or current use of antihypertensive medication.

After 12 hours of overnight fasting, the patients underwent a medical interview, physical examination with blood pressure and anthropometric measurements (height, weight, and waist circumference), and laboratory assessment. During the medical consultation, information on demographic factors, personal medical history, current medications, smoking, and postmenopausal status in women were obtained. Waist circumference was taken as the middle point between the costal margin and the iliac crest. Body mass index was calculated as weight in kilograms divided by height in meters squared. Blood pressure was measured in the sitting position, after 5 minutes of rest, using a mercury sphygmomanometer with the appropriate cuff size.

Plasma potassium was determined by ion‐selective electrodes and albumin by colorimetric method. Values of fasting plasma glucose, uric acid, total cholesterol, and triglycerides (TG) were determined by enzymatic colorimetric methods. High‐density lipoprotein (HDL) cholesterol was measured by homogeneous colorimetric enzymatic method, and low‐density lipoprotein (LDL) cholesterol was calculated by the Friedwald formula: LDL cholesterol = total cholesterol − (HDL cholesterol + TG/5). The analyzer used was Hitachi 912 (Roche Diagnostics, Basel, Switzerland). Plasma C‐reactive protein (CRP) was determined by immunochemoluminescence assay, and the kit used was Diagnostic Products Corporation Medlab (Los Angeles, CA), with analytical sensitivity of 0.01 mg/dL, intra‐assay variability of 4.2 to 6.4%, and interassay variability of 4.8 to 10%. Serum creatinine was measured through alkaline picrate assay. Renal function was determined by creatinine clearance through the Modification of Diet in Renal Disease study equation. ³⁴ Cardiovascular risk was assessed through the Framingham score proposed by the National Cholesterol Education Program in its Third Report on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) to determine the risk of a coronary event in 10 years. ³⁵

Plasma CRP was determined in 319 patients. Among them, 52 patients with CRP >1 mg/dL were not evaluated regarding this variable, due to the possibility of association with acute inflammatory processes. ³⁶

Patients were stratified into 2 major groups according to the use (T group) or lack of use (NT group) of thiazide diuretic therapy. Each group was further divided in 2 subgroups according to the presence of abdominal obesity, defined as a waist circumference ≥88 cm in women and ≥102 cm for men as proposed by the NCEP ATP III criterion for metabolic syndrome diagnosis. ³⁵ Therefore, within each major group of patients there were subgroups of patients with (AO subgroup) and without abdominal obesity (NAO subgroup)

STATISTICAL ANALYSES

The 2 major groups (T and NT groups) were analyzed separately. Within each group, continuous variables with normal distribution were analyzed by Student t test to compare AO and NAO subgroups. Only the continuous variable plasma CRP was not normally distributed and was analyzed through the nonparametric Mann‐Whitney test. Chi‐square test analyzed the association of categoric variables. Continuous variables normally distributed were expressed as mean ± SD, CRP was expressed as median and interquartile range, and categoric variables were expressed in percentages.

Two separate multiple linear regressions were performed in all patients. In the first, serum potassium was considered the dependent variable while waist circumference, thiazide use, and use of angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) were the independent variables. In the second analysis, plasma glucose was the dependent variable and waist circumference, thiazide use, ACEI or ARB use, and plasma potassium were the independent variables. Statistical significance was determined as P<.05. Statistical analyses were performed using SPSS version 12.0 software for Windows (SPSS, Inc, Chicago, IL).

RESULTS

Table I shows clinical characteristics of all patient subgroups. Except for the frequency of women, there were no differences concerning age, smoking, postmenopausal status, or arterial hypertension when comparing the 2 subgroups of patients (AO and NAO) within each group (T and NT). Moreover, no differences in the doses of thiazide diuretics were observed between the patients in AO and NAO subgroups within the T group. All patients were chronically treated with antihypertensive medications for a period longer than 1 year. In the T group, the majority of patients were receiving hydrochlorothiazide (90.5% in NAO subgroup and 92.3% in AO subgroup; not significant) in dosages of 12.5 mg/d (19.4%), 25 mg/d (77.9%), and 50 mg/d (2.7%). These were similar in both subgroups. Only 9.5% and 7.7% of the NAO and AO subgroups, respectively, were receiving chlorthalidone therapy in dosages of 12.5 mg/d (32.2%) and 25 mg/d (67.8%). The thiazide group included patients with more severe hypertension; a greater percentage of them were receiving other classes of antihypertensive drugs when compared with the non‐thiazide group (ie, ACEIs and ARBs [71.8% vs 48.2%; P<.001], calcium‐channel blockers [32.4% vs 17.0%; P=.002] and β‐blockers [25.5% vs 12%; P=.002]. However, no differences in antihypertensive therapy were observed between obese and nonobese patients within each group, indicating that the severity of hypertension was similar between the subgroups as shown in Table I.

Table I.

Comparison of Clinical Characteristics in Hypertensive Patients According to the Use of Thiazide Diuretics and NCEP Criteria for Waist Circumference Measurement

	NT Group		P Value	T Group		P Value
	NAO Subgroup (n=67)	AO Subgroup (n=74)		NAO Subgroup (n=74)	AO Subgroup (n=114)
Age, ya	56.7±11.4	57.1±10.8	.827	58.6±10.4	57.2±8.5	.319
Women, (%)	59.7	85.1	.001	62.0	93.8	<.001
Postmenopausal, (%)	73.0	76.6	.689	80.9	79.0	.796
ACEI and/or ARB use, (%)	41.8	54.1	.146	72.0	71.0	.775
β‐Blocker use, (%)	16.4	8.1	.130	28.4	23.7	.471
Calcium channel blocker use, (%)	19.4	14.8	.474	36.4	29.8	.340
Current smoker, (%)	13.4	8.1	.306	8.1	7.9	.958
Metabolic syndrome, (%)	7.4	54.0	<.001	9.4	52.6	<.001
BMI, kg/m2 a	24.6±3.2	31.4±4.1	<.001	25.7±3.0	32.7±4.8	<.001
SBP, mm Hga	140.5±19.0	137.8±16.0	.356	140.2±17.8	139.0±19.4	.681
DBP, mm Hga	86.6±10.9	85.7±8.4	.567	86.6±11.1	87.8±9.6	.676
Abbreviations: ACEI, angiotensin‐converting‐enzyme inhibitor; AO subgroup, patients with abdominal obesity; ARB, angiotensin receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; NAO subgroup, patients without abdominal obesity; NCEP, National Cholesterol Education Program; NT group, patients not receiving thiazide therapy; SBP, systolic blood pressure; T group, patients receiving thiazide therapy. aMean ± SD.

Table II lists the patient's metabolic characteristics, cardiovascular risk, and renal function. The presence of abdominal obesity was associated with higher uric acid levels, CRP values, and Framingham cardiovascular risk score in both T and NT groups. Most of the patients were classified in the low‐ and intermediate‐risk categories. However, abdominal obesity was associated with higher plasma glucose and lower plasma potassium only in the T group (Figure). In the T group, 8.3% developed hypokalemia, defined as a plasma potassium level <3.6 mEq/L (4% in the NAO‐T and 4.3% in the AO‐T subgroups). None of them showed evidence of gastrointestinal losses of potassium. Conversely, in the NT group, plasma HDL cholesterol values were lower, and the TG/HDL cholesterol ratio was higher in the AO than in the NAO subgroup.

Table II.

Comparison of Laboratory Parameters According to the Use of Thiazide Diuretics and the NCEP Criteria for Waist Circumference Measurement

	NT Group		P Value	T Group		P Value
	NAO Subgroup (n=67)	AO Subgroup (n=74)		NAO Subgroup (n=74)	AO Subgroup (n=114)
Framingham score	12.9±4.7	14.5±4.3	.038	13.8±3.7	15.2±3.5	.010
Creatinine clearance, MDRD	73.2±12.7	72.4±13.8	.719	72.5±9.5	69.7±11.5	.070
C‐reactive protein, mg/La	0.15 (0.08–0.31)	0.32 (0.17–0.48)	<.001	0.13 (0.08–0.24)	0.38 (0.18–0.58)	<.001
Fasting plasma glucose, mg/dL	83.7±11.8	86.0±9.8	.206	84.8±8.4	87.7±10.9	.039
Uric acid, mg/dL	5.1±1.5	5.6±1.4	.045	5.2±1.4	5.7±1.4	.015
Serum potassium, mEq/L	4.5±0.41	4.5±0.44	.784	4.4±0.50	4.2±0.45	.013
Total cholesterol, mg/dL	217.5±37.2	218.5±36.7	.877	208.6±36.1	214.7±39.0	.289
HDL cholesterol, mg/dL	62.9±17.7	56.0±12.9	.010	61.6±18.5	57.8±11.2	.115
LDL cholesterol, mg/dL	129.9±33.6	133.4±34.7	.436	117.5±29.4	126.7±34.9	.061
TG, mg/dL	129.0±60.0	146.0±65.5	.117	140.4±75.0	143.8±57.1	.732
TG/HDL cholesterol ratio	2.28±1.33	2.86±1.77	.032	2.62±1.82	2.64±1.30	.948
Abbreviations: AO subgroup, patients with abdominal obesity; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MDRD, Modification of Diet in Renal Disease equation; NCEP, National Cholesterol Education Program; NAO subgroup, patients without abdominal obesity; NT group, patients not receiving thiazide therapy; T group, patients receiving thiazide therapy; TG, triglycerides. Values are mean ± SD unless otherwise indicated. aValues are median and interquartil range.

Figure.

Comparison of plasma potassium, plasma glucose, and triglyceride (TG)/high‐density lipoprotein (HDL) cholesterol ratio between patients with (AO+) and without abdominal obesity (AO−) divided according to diuretic therapy status.

Considering all patients together, 2 distinct multiple linear regressions were performed and the interactions among the variables were tested. In the first, we evaluated the influence of waist circumference, thiazide use, and ACEI or ARB use on plasma potassium values. In the second analysis, we examined the influence of waist circumference, thiazide use, ACEI or ARB use, and plasma potassium on plasma glucose. The findings from the first regression model showed that waist circumference (P=.041) and use of thiazides diuretics (P<.001) were independently associated with plasma potassium values, while the second regression analysis showed that waist circumference (P=.046) and serum potassium (P=.034) were independently associated with plasma glucose abnormalities.

DISCUSSION

In our study, the association of abdominal obesity with higher plasma CRP levels, uric acid concentrations, and Framingham score in both T and NT groups are in accordance with previous findings that consider obesity a condition of subclinical chronic inflammation ³⁷ and central fat distribution a risk factor for cardiovascular diseases. ⁶ There is a strong association between CRP and total and abdominal obesity, ³⁸ since the adipocites ³⁹ and macrophages, mainly in omental adipose tissue, produce interleukin 6, which in turn induces CRP synthesis in the liver. ⁴⁰ Elevated serum uric acid levels have been related to obesity. ⁴¹ Impaired urate renal clearance, induced by hyperinsulinemia, may be the mechanism in individuals with insulin resistance. ⁴² In our study, diuretic therapy did not interfere in the differences observed between patients with and without abdominal obesity. Although the Framingham score was higher in patients with abdominal obesity, they were classified in the low‐and intermediate‐risk categories. This may be in part due to the fact that diabetic patients, who are considered to be in the high‐risk category for coronary artery disease, were not included. Another explanation would be that the Framingham point scoring system may underestimate the coronary artery disease risk of obese patients with the metabolic syndrome. It assesses a low short‐term risk and does not consider many of the elements of the syndrome, which could be important in evaluating coronary artery disease risk over a period longer than 10 years. ⁴³

Recent studies have described a functional RAS located in adipose tissue, with expression of many of the RAS components. ¹¹ , ¹⁵ , ¹⁶ , ¹⁷ In our study, only obese patients receiving diuretic therapy had lower plasma potassium levels, suggesting that abdominal obesity predisposes to potassium depletion during diuretic therapy and that RAS activation could be involved. Concerning glucose metabolism, our obese, hypertensive, nondiabetic patients had higher plasma glucose levels in association with lower plasma potassium values (although within the normal range) during diuretic therapy. Considering all patients together, linear regressions also indicated that thiazide use and abdominal obesity independently predispose to reductions in plasma potassium, with further repercussions on glucose homeostasis. These findings are in accordance with previous reports describing even mild potassium depletion as a mechanism leading to glucose intolerance in patients receiving thiazide diuretics. ²⁷ , ²⁸ Helderman and associates ²⁶ demonstrated that oral potassium supplementation prevented glucose intolerance during diuretic therapy and also suggested that changes in glucose metabolism induced by diuretic therapy were attributed to potassium depletion.

The increased risk of diabetes associated with the use of thiazides compared with other therapies has been described in several studies. ²³ , ²⁴ Verdecchia and associates ⁴⁴ demonstrated that baseline fasting plasma glucose and diuretic treatment were independent predictors of new‐onset diabetes in a small population of hypertensive patients followed for 6 years. Of importance, however, the use of diuretics did not adversely affect cardiovascular outcome. These data are also consistent with findings from the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in which a diuretic‐based treatment program (with a β‐blocker added if necessary) resulted in 3.5% more new‐onset diabetes cases than an ACEI‐based treatment regimen; there were, however, no differences in coronary heart disease outcomes between the ACEI and diuretic groups. ²³ It is possible, however, that a longer period of follow‐up might be necessary to assess cardiovascular outcome.

It was described previously that the metabolic effect of small doses of a diuretic may be blunted by the concomitant use of an ACEI. ⁴⁵ However, our results indicate that abdominal obesity may predispose to thiazide‐induced changes in serum potassium and plasma glucose, even during use of ACEIs or ARBs.

In the group of patients who did not receive a diuretic, it was observed that the TG/HDL cholesterol ratio was higher in the obese, suggesting that they were more insulin‐resistant than the nonobese subgroup. According to previous studies, an increased TG/HDL cholesterol ratio is a metabolic marker of insulin resistance. ⁴⁶ In the T group, no differences in the TG/HDL cholesterol were found between the 2 subgroups, suggesting a similar state of insulin resistance, possibly related to antihypertensive therapy (diuretic and β‐blockers)

CONCLUSIONS

Abdominal obesity appears to be associated with potassium depletion and changes in glucose homeostasis during diuretic therapy, suggesting that an RAS‐related mechanism for hypertension could be involved. Therefore, particularly in obese insulin‐resistant patients, the choice of thiazide diuretic therapy should take into account not only its effects on blood pressure but also its possible influence on the plasma potassium, glucose, and lipid profiles.