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We assessed adverse metabolic effects (AMEs) of atenolol and hydrochlorothiazide (HCTZ) among hypertensive patients with and without abdominal obesity using data from a randomized, open-label study of hypertensive patients without evidence of cardiovascular disease or diabetes. Intervention included randomization to HCTZ 25mg or atenolol 100mg monotherapy followed by their combination. Fasting glucose, insulin, triglycerides, HDL cholesterol and uric acid were measured at baseline and after mono-and combination therapy. Outcomes included new occurrence of and predictors for new cases of glucose ≥ 100mg/dl (impaired fasting glucose [IFG]), triglyceride ≥ 150 mg/dl, HDL ≤ 40mg/dl for men or ≤ 50mg/dl for women, or new onset diabetes according to presence or absence of abdominal obesity. Abdominal obesity was present in 167/395 (58%). Regardless of strategy, in those with abdominal obesity, 20% had IFG at baseline compared with 40% at end of study (p<0.0001). Proportion with triglycerides ≥ 150 mg/dl increased from 33% at baseline to 46% at end of study (p<0.01). New onset diabetes occurred in 13 (6%) with and in 4 (2%) without abdominal obesity. Baseline levels of glucose, triglyceride and HDL predicted adverse outcomes and predictors for new onset diabetes after monotherapy in those with abdominal obesity included HCTZ strategy (OR 47, 95% CI 2.55-862), female sex (OR 31.3, 95% CI 2.10-500) and uric acid (OR 3.2, 95% CI 2.35-7.50). Development of AME, including new onset diabetes associated with short term exposure to HCTZ and atenolol was more common in those with abdominal obesity.
It is estimated that more than 72 million US adults are obese, affecting 33% of men and 35% of women.1 This epidemic is associated with increased mortality,2 primarily via metabolic and cardiovascular complications. Abdominal fat accumulation increases cardiovascular disease (CVD) risk independent of overall adiposity.3 The presence of abdominal obesity provides additional predictive information for the development of CV morbidity and mortality, compared to increased body mass index alone.4
Hypertension requiring treatment is highly prevalent in those with obesity and abdominal obesity, regardless of sex or ethnicity, and is poorly controlled.5–7 Some antihypertensives are associated with adverse metabolic effects (AMEs), including hyperglycemia, hypertriglyceridemia and hyperuricemia.8 The predisposing factors for these AMEs are unknown, but pre-existing abdominal obesity may contribute. While there are many studies in older, high risk populations indicating thiazide diuretics and β blockers increase the incidence of new onset diabetes compared with other antihypertensive regimens,9 our knowledge is incomplete with regard to the development of AMEs in those with a lower CV risk profile, and the contribution of abdominal obesity to this risk.
Accordingly, we investigated early AMEs and clinical characteristics predictive of early AMEs among those with and without abdominal obesity in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We hypothesized that antihypertensive induced AMEs develop preferentially in those with abdominal obesity.
This study includes analysis of the AMEs data from a contemporary population of low risk hypertension subjects enrolled in the PEAR study. PEAR is an ongoing, prospective, randomized, parallel group titration study undertaken primarily to evaluate the pharmacogenomic determinants of the antihypertensive and adverse metabolic responses to hydrochlorothiazide (HCTZ) and atenolol in hypertensive patients without a history of heart disease or diabetes. Details regarding study design and enrollment criteria have been previously published.10 PEAR is registered at ClinicalTrials.gov, #NCT00246519;URL: http://clinicaltrials.gov/ct2/show/NCT00246519.
Men and women with mild to moderate essential hypertension age 17 to 65 are being recruited from primary care populations at the University of Florida (Gainesville, FL), Emory University (Atlanta, GA) and Mayo Clinic (Rochester, MN). Enrolled subjects had newly diagnosed, untreated or treated hypertension. Those in whom hypertension was treated, had antihypertensives discontinued with a minimum washout of 18 days.
The study has been conducted in accordance with the provisions of the Declaration of Helsinki, and was approved by the Institutional Review Boards at each institution. Written informed consent was provided by each patient prior to participation. Those meeting the BP inclusion criteria were randomized at each study site to receive HCTZ or atenolol. HCTZ and atenolol were initiated at 12.5mg and 50mg daily, respectively, and titrated to 25mg and 100mg daily, based on BP. After at least 6 weeks of HCTZ 25mg or atenolol 100mg, or maximum tolerated dose, response to monotherapy was assessed. Then, those with BP remaining > 120/70 mmHg had the second drug added and titrated to maximum dose. Response to combination therapy was assessed after 6 weeks on both drugs at maximum tolerated dose.
Height and weight were measured to the nearest 0.1 centimeter and 0.1 kilogram, respectively. Waist circumference was measured to the nearest 0.5 centimeter, by placing a tape measure snugly around the abdomen at the level of the umbilicus just above the uppermost lateral border of the right iliac crest and at the normal minimal respiration with the patient in standing position and his/her hands by the side. Patients were categorized as having abdominal obesity if their waist measured ≥ 35 inches for women or ≥ 40 inches for men.11
At baseline, fasting blood samples were collected for glucose, insulin, potassium, magnesium, uric acid, and a lipid profile. Blood samples were collected again, after a 12 hour fast, at the completion of the mono- and combination therapy phases of the study. Insulin sensitivity using homeostatsis model assessment-insulin resistance (HOMA-IR) was calculated at each time point according to a validated formula.12 Estimated GFR was calculated using the MDRD equation.13
Serum potassium, magnesium, glucose, triglyceride, HDL cholesterol, and uric acid concentrations were measured on an Hitachi 911 Chemistry Analyzer (Roche Diagnostics, Indianapolis IN) at the central laboratory at Mayo Clinic. Potassium and magnesium concentrations were determined by an ion selective electrode, and glucose, triglycerides, HDL cholesterol and uric acid concentrations were determined spectrophotometrically by automated enzymatic assays. LDL cholesterol was computed. Plasma insulin was measured using the Access® Ultrasensitive Insulin immunoassay system (Beckman Instruments, Chaska MN). All samples were tested in duplicate and data reported are the mean of the duplicate samples.
Within abdominal obesity categories, we compared the percentage of patients with glucose < 100mg/dl and ≥ 100mg/dl, triglycerides < 150mg/dl and ≥ 150mg/dl, and HDL <40 for male, <50 for female (hereafter termed low HDL)or ≥40 for male, ≥50 for female at baseline and after mono- and combination therapy in the two treatment strategies. These categories were picked based on their inclusion in the definition of MetSyn.11 Additionally we compared the percentage of patients with incident diabetes (fasting glucose ≥ 126mg/dl) after mono- and combination therapy within waist groups and treatment strategies. Lastly, we assessed the clinical characteristics that were predictive for development of these outcomes following monotherapy, in those in whom the outcomes were absent at baseline.
Nonparametric tests were used when data was non-normally distributed. Baseline characteristics were compared between patients with and without abdominal obesity using Chi-square and Wilcoxon rank-sum tests. McNemar test was used to compare counts of dichotomous traits of MetSyn criteria in the abdominal obesity groups before and after treatment. Continuous variables repeatedly measured over time were compared using Friedman's test.
We used a multivariable logistic regression analysis to determine factors associated with having a glucose level ≥ 100 mg/dL after monotherapy among those with a level < 100 mg/dL at baseline. Patient’s baseline clinical characteristics and laboratory variables were entered in a backward logistic regression model. Variables with a p-value of less than 0.05 were retained in the model. The same logistic regression analysis was performed for triglycerides ≥150 mg/dL, low HDL, and new onset diabetes. The baseline variables entered in the model were: age, sex, race, treatment strategy, waist status, pulse, home BP, glucose, insulin, triglyceride, uric acid, HDL, LDL, potassium, estimated GFR and current smoking status. Because potassium during treatment with HCTZ has been associated with dysglycemia, on-treatment change in potassium was also entered in the model.
All statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, NC). P value less than 0.05 was considered significant for a single test. For multiple comparisons we used the Bonferroni adjustment and the critical P value was 0.017 after adjustment.
From a total of 418 patients who had completed PEAR at the time of this analysis, we excluded those with missing waist circumference measurements (n=13), and those with nonfasting laboratory measurements (n=10). Baseline characteristics of the 395 patients included in this analysis are summarized in Table 1, according to the presence or absence of abdominal obesity. Among these middle-aged hypertensive patients, 58% had abdominal obesity. At baseline, compared to those without abdominal obesity, those with abdominal obesity had significantly higher fasting glucose, insulin, HOMA-IR, triglycerides and lower HDL. They were also significantly more likely to have MetSyn compared with those without abdominal obesity (OR 10.1, 95% CI 6.13-16.57). Less than one quarter of all patients had impaired fasting glucose. Mean duration of antihypertensive washout was 29 ± 16 days, and there was no difference in any of the metabolic parameters of interest at baseline comparing those who had received prior treatment with a β blocker and/or thiazides diuretic and those who had received other classes of antihypertensive agents. Mean duration of mono- and combination therapy in each of the treatment strategies was 9 weeks resulting in a mean total follow-up of 18 weeks for all patients. In the atenolol strategy, 86% of patients were taking atenolol 100mg, and 78% of patients were taking HCTZ 25 mg at the end of combination therapy. In the HCTZ strategy, 98% of patients were taking HCTZ 25mg and 68% of patients were taking atenolol 100 mg at the end of combination therapy. There were not significant differences comparing percentage on maximum dose between those with and without abdominal obesity.
Table 2 summarizes mean biochemical, BP parameters and weight according to treatment strategy in those without and with abdominal obesity. In those randomized to the atenolol strategy (top half of table), glucose, triglycerides and uric acid were significantly increased during follow-up irrespective of presence or absence of abdominal obesity at baseline. In those randomized to the HCTZ strategy (bottom half of table), uric acid was significantly increased during follow-up irrespective of presence or absence of abdominal obesity at baseline. However, in the HCTZ strategy, those with abdominal obesity at baseline also exhibited significantly increased glucose, insulin, HOMA-IR and triglycerides during follow-up. Insulin and HOMA-IR were not significantly affected by monotherapy or combination therapy in either treatment strategy in the group without abdominal obesity, nor were they affected in those with abdominal obesity treatment with the atenolol strategy.
Regardless of abdominal obesity status, potassium was significantly decreased in both treatment strategies, related to initiation of or add-on HCTZ, although mean potassium did not fall below 4.0 meq/l. There was not a difference in potassium decrease in those with and without abdominal obesity following HCTZ monotherapy (p=0.96) or add-on therapy (p=0.08). Systolic and diastolic BP and pulse were significantly and similarly decreased by both treatment strategies, while weight was not significantly affected by either strategy.
In subjects without abdominal obesity (Figure 1, left side), the majority had glucose < 100mg/dl, high HDL, and triglycerides < 150mg/dl at baseline. While neither treatment strategy significantly altered the proportion of patients with glucose ≥ 100mg/dl, drug treatment significantly increased the proportion with low HDL and triglycerides ≥ 150mg/dl.
In subjects with abdominal obesity (Figure 1, right side), both treatment strategies resulted in significantly increased proportions with glucose ≥ 100mg/dl, approximately doubling following combination therapy. The proportion with triglycerides ≥ 150mg/dl increased by 30–50% following combination therapy. Order of initiation (atenolol vs HCTZ) did not impact the glucose or triglyceride outcomes within either abdominal obesity group.
A total of 17 patients developed new onset diabetes during the follow-up period. In the abdominally obese patients, new onset diabetes occurred in 13/224 (6%) patients, 11 patients in the HCTZ strategy and 2 patients in the atenolol strategy (p=0.0189). In those without abdominal obesity, 4/164 (2%) patients developed new onset diabetes, 2 patients in the HCTZ strategy and 2 patients in the atenolol strategy, (p=1.00). Of the 17 patients who developed new onset diabetes, 13 (76%) met the criteria for MetSyn at baseline, and mean baseline fasting glucose was 101 ± 11.8 mg/dl.
Table 3 summarizes baseline predictors of developing glucose ≥ 100mg/dl, triglycerides ≥ 150mg/dl, low HDL or new onset diabetes following exposure to atenolol or HCTZ monotherapy in those in whom the condition was not present at baseline.
Multiple randomized controlled studies in patients with or at increased risk for CVD have associated long term use of thiazide diuretics and/or β blockers with new onset diabetes compared to other antihypertensive medications.9 Our findings in a contemporary sample of hypertensives without CVD or diabetes demonstrate that the AMEs of atenolol and HCTZ begin within 9 weeks of initiation, and are most pronounced in patients with abdominal obesity with longer duration of exposure to HCTZ. Importantly, in patients with abdominal obesity, we observed a significant increase in the proportion with adverse metabolic phenotypes including impaired fasting glucose, increased triglycerides and low HDL, which are known to increase the risk of developing diabetes and long term CV adverse outcomes.
In PEAR participants with hypertension and abdominal obesity, we observed significantly higher baseline values for glucose, insulin and triglycerides, lower HDL values as well as prevalence of metabolic syndrome compared with those without abdominal obesity, indicating a population at increased risk for developing diabetes.14,15 Following 9 – 18 weeks of exposure to HCTZ 25mg either alone or in combination with atenolol, patients with abdominal obesity had a significant increase in glucose and a significant increase in the proportion with glucose ≥ 100mg/dl or impaired fasting glucose. While the notion that treatment with thiazide diuretics increases glucose and worsens glucose tolerance is not new,16 it is considered by some to be an "innocent" side effect that takes many years to develop and may not be associated with adverse CV outcomes.17,18 Others have shown a significant association between antihypertensive associated incident diabetes and CV outcomes including stroke, myocardial infarction and death.19,20 Importantly, in patients who have both abdominal obesity and hypertension, a glucose ≥ 100mg/dl results in a diagnosis of MetSyn,11 resulting in a 3- to 5 fold increase in the risk for diabetes.15 Risk for longterm CV morbidity and mortality is increased 2- to 4 fold, and increases proportionately with increasing number of MetSyn components,21 suggesting the importance of preventing or aggressively treating each of the MetSyn criteria. Among our patients, who were exposed to short term antihypertensive therapy, the majority who developed diabetes also had MetSyn and impaired fasting glucose at baseline.
The hyperglycemic effects of thiazide diuretics have been associated with diuretic induced hypokalemia,22,23 however, we did not confirm this association in PEAR participants.24 In a cross-sectional study, serum potassium was found to be independently associated with plasma glucose abnormalities in abdominally obese hypertensives treated with thiazide diuretics.25 The data presented here did not confirm this finding, as neither baseline potassium nor change in potassium during treatment predicted development of either impaired fasting glucose or new onset diabetes.
Visceral fat may influence metabolism and promote insulin resistance via the liver through the portal circulation, and recently, treatment with HCTZ for 12 weeks was associated with liver fat accumulation and fat redistribution from the subcutaneous to the visceral space in patients with abdominal obesity.26 This fat redistribution was associated with aggravated insulin resistance and low grade inflammation. This mechanism may partially explain the insulin resistance we observed in our abdominally obese subjects assigned to the HCTZ strategy but not in those assigned to the atenolol strategy.
While the number of cases of new onset diabetes we report here is small, when extrapolated to the large population of abdominally obese individuals with hypertension who are likely to be exposed to HCTZ and/or atenolol, the impact is significant. Baseline predictors of new onset diabetes during treatment with antihypertensives in long term observational and prospective treatment trials consistently include age, Hispanic ethnicity, BMI, waist circumference, glucose (fasting and nonfasting), HDL, female sex, and treatment with a thiazide diuretic and/or β blocker.27 In PEAR, baseline predictors of new onset diabetes following short term use of antihypertensives are remarkably consistent with this list. Importantly, we add an additional predictive factor, uric acid, which was associated with a more than 3 fold excess risk of new onset diabetes. Baseline uric acid was also a significant predictor of elevated triglycerides post treatment in PEAR. Additionally, during follow-up, we observed a significant increase in uric acid without regard to abdominal obesity status, particularly associated with the addition of HCTZ. This uric acid elevation may have serious long term consequences in terms of increased risk of CV events, as well as offsetting benefits of BP lowering.28
There are some limitations of this study worthy of mention. We only measured fasting glucose and not glucose tolerance based on the outcome of an oral glucose tolerance test. As a result, we likely under detected new onset diabetes cases which might have been diagnosed based on impaired glucose tolerance, which has been associated with short term use of HCTZ.29 This may also have contributed to the wide confidence intervals observed in Table 3, and thus should be interpreted with some caution. We are unable to adequately assess the impact of dose of HCTZ or atenolol on development of AMEs, since the majority of all patients in both treatment strategies required the highest protocol specified dose (HCTZ 25mg and atenolol 100mg). It has been suggested that the AMEs associated with HCTZ are dose related and are minimized or prevented with lower doses than used in this study, however PEAR data suggest few patients achieve their BP goal with HCTZ 12.5mg daily.30 Additionally, lower doses of thiazides have been associated with neutral or negative long term morbidity and mortality outcomes, and thus may not be optimal long term treatments. Similarly, due to the lack of a control (untreated) group, we are unable to detect temporal changes that might have occurred even without treatment. Lastly, we only have a single fasting blood glucose of ≥ 126 mg/dl in patients classified as having new onset diabetes.
In conclusion, we observed AMEs, including new onset diabetes in a contemporary sample of hypertensive study participants following only short term treatment with HCTZ and atenolol. These adverse effects were more prominent in those with abdominal obesity, depite normal potassium levels. Our findings reinforce guidelines and recommendations that indicate thiazide diuretics and β blockers be used with caution in patients with or at risk for developing impaired fasting glucose or MetSyn, in order to prevent the development of diabetes and the associated long term adverse consequences.31,32
New data from the Centers For Disease Control and Prevention indicate that in the US, the prevalence of obesity in whites ranges from 9 to 30%. Compared with whites, blacks had 51% higher, and Hispanics had 21% higher prevalence of obesity.33 Given that approximately 50% of obese individuals also have hypertension,5–7 understanding the impact the AMEs of thiazide diuretics and β blockers in this growing population is important. Our data add significantly to the growing body of literature related to the metabolic effects of antihypertensives by demonstrating that the AMEs associated with both thiazide diuretics and β blockers occur very early in therapy in those with abdominal obesity, and in our population of hypertensives with abdominal obestiy, HCTZ was strongly associated with new diabetes following just 9–18 weeks of exposure. Because treatment for hypertension usually requires life-long therapy, and the likelihood of developing AMEs increases with increasing exposure duration, particularly to HCTZ, prescribers should consider not only the BP lowering properties, but also the AMEs which could include diabetes and it’s associated CV outcomes, when developing a hypertension treatment regimen for patients with abdominal obesity and/or MetSyn.
RCD and SW had full access to all of the data used in this study and take full responsibility for the integrity of the data and the accuracy of the data analysis. We acknowledge and thank the valuable contributions of the study participants, support staff, and study physicians: Drs. George Baramidze, Carmen Bray, Kendall Campbell, Robert Whit Curry, Frederic Rabari-Oskoui, Dan Rubin, and Siegfried Schmidt.
SOURCE OF FUNDING
This work is supported by a grant from the National Institutes of Health (Bethesda, MD), grant # U01 GM074492, funded as part of the Pharmacogenetics Research Network. Additionally this work is supported by the following grants from the National Institutes of Health, National Center for Research Resources: M01 RR00082 to the University of Florida, UL1 RR025008 and M01 RR00039 to Emory University, and UL1 RR024150 to Mayo Clinic, and the National Heart Lung and Blood Institute K23HL08655 (Cooper-DeHoff) and K23HL091120 (Beitelshees).
Conflict of Interest
IZ is an employee of the U.S. FDA, and the views expressed in this manuscript do not necessarily reflect the official policy of the FDA. No official endorsement by the FDA is intended or should be inferred.