Impaired Fasting Glucose in Hypertensive Patients: Prevalence and Cross-Sectional Analysis of Associations with Cardiovascular Disease

Abstract

Background:

Impaired fasting glucose (IFG) is frequently present in hypertensive patients and might be induced or aggravated by antihypertensive treatment. However, it is unclear whether IFG is associated with increased cardiovascular risk in this population.

Patients and Methods:

We performed a cross-sectional study in 1,810 hypertensive patients and recorded the presence of IFG, coronary heart disease (CHD), and ischemic stroke.

Results:

IFG was present in 567 patients (31.3%). The prevalence of CHD or ischemic stroke did not differ between patients with IFG and in patients with serum glucose levels <100 mg/dL. Among patients with IFG, 267 (47.0%) were on β-blockers, diuretics, or both β-blockers and diuretics. The prevalence of CHD was numerically but not significantly higher in patients with IFG treated with β-blockers or both β-blockers and diuretics than in patients with IFG treated with diuretics or not treated with either β-blockers or diuretics and patients with serum glucose levels <100 mg/dL (11.1%, 13.6%, 1.4%, 3.7%, and 5.9%, respectively; P=not significant). The prevalence of ischemic stroke did not differ among these groups.

Conclusions:

IFG does not appear to be associated with increased prevalence of cardiovascular disease in hypertensive patients, regardless if it is associated with the antihypertensive treatment or not.

Introduction

I mpaired fasting glucose (IFG) is defined as fasting plasma glucose levels between 100 and 125 mg/dL.¹ IFG affects approximately 8% of adults worldwide.^2
–4 Moreover, IFG is considered a prediabetes condition (i.e., is associated with increased risk for progression to type 2 diabetes mellitus [T2DM]).⁵ The annual incidence of T2DM in patients with IFG ranges between 6.1% and 9.2%.⁵ Nevertheless, despite the strong relationship between T2DM and cardiovascular disease (CVD),^6
–8 IFG appears to be associated with only a modest increase in CVD risk.⁹

The prevalence of both IFG and T2DM is higher among hypertensive patients than in the general population.^10

–13 In addition, specific classes of antihypertensive agents, namely, β-blockers and diuretics, further increase the risk for T2DM in hypertensive patients.^14
–16 Nevertheless, it is still controversial whether T2DM that develops during treatment with these agents increases CVD risk.^17

–22 Moreover, there is a paucity of data regarding the association between IFG that develops during antihypertensive treatment and CVD risk.

The aim of the present study was to assess the prevalence of IFG in a large cohort of hypertensive patients followed up in the outpatient clinics of a university department. We also aimed to evaluate the association between IFG and CVD in hypertensive patients treated with β-blockers and/or diuretics and in patients not treated with these agents.

Patients and Methods

We studied the medical records of the last visit of all patients who attended at least once the hypertension outpatient clinic of our Department during the last decade (2002–2011) (n=1,810; 40.4% males; age, 56.5±13.5 years).

Clinic blood pressure measurements were performed according to current guidelines.²³ At minimum, two measurements were performed for each patient, and the average was recorded. In all patients, weight, height, and waist circumference were measured. Body weight was measured with an analog scale and in light clothing; height was measured barefoot with a stadiometer. Body mass index (BMI) was calculated by dividing weight (in kg) by height (in m) squared. The waist circumference was measured at the smallest circumference at the level of the umbilicus.

Blood samples were collected in the morning after a 12-h fast. Serum glucose, total cholesterol, high-density lipoprotein cholesterol, triglycerides, and creatinine levels were determined. Low-density lipoprotein cholesterol (LDL-C) levels were calculated using the formula of Friedewald et al.²⁴ Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation.²⁵

Coexisting conditions, including coronary heart disease (CHD), ischemic stroke, and smoking, were defined based on self-report. T2DM was defined as fasting serum glucose levels >125 mg/dL or a previous diagnosis by a physician. IFG was defined as fasting serum glucose levels 100–125 mg/dL.¹

Statistical analysis

All data were analyzed using the statistical package SPSS (version 17.0; SPSS, Inc., Chicago, IL). All continuous variables followed normal distribution as assessed with the Kolmogorov–Smirnov test. Data are presented as mean and SD values. Differences in categorical variables between groups were assessed with the χ² test. Differences in continuous variables between groups were assessed with one-way analysis of variance, and post hoc tests were carried out with the Holm–Sidak test. In patients with IFG, binary logistic regression analysis was performed including established CVD risk factors (age, gender, smoking, and serum LDL-C and high-density lipoprotein cholesterol levels), serum glucose levels, and type of antihypertensive medication as independent variables and CHD as the outcome. In all cases, a two-tailed P<0.05 was considered significant.

Results

Two hundred ninety-five patients had T2DM (16.3%), and 567 patients (31.3%) had IFG. The characteristics of patients with IFG and of patients with serum glucose levels <100 mg/dL are shown in Tables 1 and 2. The BMI, waist circumference, and the prevalence of overweight and obesity did not differ between patients with IFG and those with serum glucose levels <100 mg/dL. Patients with IFG were older and had higher serum LDL-C levels than patients with serum glucose levels <100 mg/dL (P<0.05 and P<0.005, respectively). However, the prevalence of CHD did not differ between the two groups (4.7% and 5.9% in patients with IFG and in patients with serum glucose levels <100 mg/dL, respectively; odds ratio [OR] 1.26, 95% confidence interval [CI] 0.62–2.55, P=not significant). The prevalence of ischemic stroke was also similar in patients with IFG and in patients with serum glucose levels <100 mg/dL (3.2% and 4.0%, respectively; OR 1.28, 95% CI 0.54–3.01, P=not significant).

Table 1.

Characteristics of Patients with Impaired Fasting Glucose and of Patients with Serum Glucose Levels <100 mg/dL

	Patients with
	Impaired fasting glucose (n=567)	Serum glucose levels <100 mg/dL (n=948)	P	OR (95% CI)
Age (years)	57.6±12.9	54.9±14.1	<0.05	2.70 (0.54, 4.86)
Males	39.9	36.8	0.417	0.88 (0.64, 1.21)
Smoking	25.3	23.8	0.665	0.92 (0.64, 1.32)
Pack-years	10±15	14±26	0.444	−3.92 (−14.06, 6.22)
Overweight or obese	91.1	83.1	0.080	0.48 (0.21, 1.09)
Coronary heart disease	4.7	5.9	0.524	1.26 (0.62, 2.55)
Ischemic stroke	3.2	4.0	0.573	1.28 (0.54, 3.01)
SBP (mm Hg)	146±22	144±20	0.168	2.31 (−0.98, 5.60)
DBP (mm Hg)	88±14	88±13	0.724	0.39 (−1.76, 2.53)
Heart rate (beats/min)	76±12	75±9	0.516	1.09 (−1.38, 2.91)
BMI (kg/m²)	30.1±4.8	30.4±6.4	0.614	−0.39 (−1.90, 1.13)
Waist circumference (cm)	102±9	99±12	0.099	3.39 (−1.07, 7.85)
TC (mg/dL)	239±67	225±59	0.05	6.87 (0.93, 27.96)
LDL-C (mg/dL)	161±63	142±52	0.005	18.57 (6.96, 30.19)
HDL-C (mg/dL)	51±13	52±14	0.245	−1.42 (−3.82, 0.98)
TG (mg/dL)	153±74	146±82	0.319	6.89 (−6.67, 20.45)
Glucose (mg/dL)	109±7	90±7	<0.001	19.13 (18.04, 20.22)
eGFR (mL/min/1.73 m²)	82±26	78±22	0.065	4.16 (−1.02, 8.13)

Data are mean±SD values or mean percentages as indicated.

BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NS, not significant; OR, odds ratio; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides.

Table 2.

Characteristics of Patients with Impaired Fasting Glucose Depending on Their Antihypertensive Treatment and of Patients with Serum Glucose Levels <100 mg/dL

	Patients with impaired fasting glucose (n=567)
	On β-blockers (n=61)	On diuretics (n=157)	On both β-blockers and diuretics (n=49)	Neither on β-blockers nor on diuretics (n=300)	Patients with serum glucose levels <100 mg/dL (n=948)	P (overall)
Age (years)	55.9±9.3	62.3±11.5	62.6±10.8	54.7±13.7	54.9±14.1	<0.001^a
Males	22.2	38.6	31.8	45.5	36.8	0.152
Smoking	25.9	20.0	27.3	27.6	23.8	0.792
Pack-years	3±1	4±1	3±1	14±18	14±26	0.716
Overweight or obese	10.0/90.0	0.0/100.0	14.3/85.7	13.0/87.0	16.9/83.1	0.219
Coronary heart disease	11.1	1.4	13.6	3.7	5.9	0.105
Ischemic stroke	3.7	4.3	4.5	2.2	4.0	0.905
SBP (mm Hg)	154±25	149±24	145±28	144±18	144±20	0.095
DBP (mm Hg)	94±15	87±15	87±15	88±12	88±13	0.258
Heart rate	80±20	76±11	72±12	75±10	75±9	0.169
BMI (kg/m²)	29.5±6.7	30.6±3.6	28.9±4.1	30.0±5.2	30.4±6.4	0.929
Waist circumference (cm)	97±10	106±7	97±11	103±9	99±12	0.250
TC (mg/dL)	225±45	258±74	196±52	241±67	225±59	<0.01^b
LDL-C (mg/dL)	152±59	180±71	122±40	159±61	142±52	<0.001^c
HDL-C (mg/dL)	49±13	51±13	46±13	52±13	52±14	0.403
TG (mg/dL)	160±72	157±61	145±51	150±84	146±82	0.792
Glucose (mg/dL)	110±6	111±7	111±8	108±6	90±7	<0.001^d
eGFR (mL/min/1.73 m²)	81±17	84±36	75±17	83±21	78±22	0.180

Data are mean±SD values or mean percentages as indicated.

Significant differences in post hoc pairwise comparisons are indicated:

On diuretics versus neither on β-blockers nor on diuretics, P<0.01; on diuretics versus patients with serum glucose levels <100 mg/dL, P<0.001.

On diuretics versus on both β-blockers nor on diuretics, P<0.05; on diuretics versus patients with serum glucose levels <100 mg/dL, P<0.05.

On diuretics versus on both β-blockers nor on diuretics, P<0.05; on diuretics versus patients with serum glucose levels <100 mg/dL, P=0.001.

On diuretics versus neither on β-blockers nor on diuretics, P<0.05; patients with serum glucose levels <100 mg/dL versus all other groups, P<0.001.

BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NS, not significant; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides.

Among the 567 patients with IFG, 267 patients (47.0%) were on β-blockers, diuretics, or both β-blockers and diuretics (n=61, 157, and 49, respectively). Characteristics of these patients and of patients with IFG who were neither on β-blockers nor or diuretics (n=300) are shown in Table 2. Patients with IFG treated with diuretics were older and had higher serum LDL-C levels than patients with serum glucose levels <100 mg/dL (P<0.001 and P=0.001, respectively). The prevalence of CHD was numerically but not significantly higher in patients with IFG treated with β-blockers or both β-blockers and diuretics than in patients with IFG treated with diuretics or not treated with either β-blockers or diuretics and patients with serum glucose levels <100 mg/dL (11.1%, 13.6%, 1.4%, 3.7%, and 5.9%, respectively; P=not significant). In binary logistic regression analysis, smoking (OR 7.58, 95% CI 1.40–41.05, P<0.05), serum glucose levels (OR 4.62, 95% CI 1.39–15.40, P<0.05), and treatment with β-blockers (OR 1.09, 95% CI 1.01–1.19, P<0.05) were independently associated with the presence of CHD. On the other hand, the prevalence of ischemic stroke did not differ among patients with IFG treated with β-blockers, diuretics, both β-blockers and diuretics, or neither β-blockers nor diuretics and patients with serum glucose levels <100 mg/dL (3.7%, 4.3%, 4.5%, 2.2%, and 4.0%, respectively; P=not significant).

Discussion

In the present study, almost one-third of hypertensive patients (31.3%) had IFG. This rate is comparable with previous reports in hypertensive patients^10,11 and considerably higher than the reported prevalence of IFG in the general population, where it is approximately 8%.⁵ However, hypertensive patients with IFG did not have a higher prevalence of CHD or ischemic stroke than patients without IFG. Moreover, this lack of difference in CVD rates between patients with and without IFG was observed despite the fact that patients with IFG were older and had higher serum LDL-C levels; other CVD risk factors did not differ between the two groups. In discordance with our findings, a recent meta-analysis of 102 prospective studies in 698,782 subjects without established CVD reported a modestly increased CHD risk between subjects with serum glucose levels of 100–110 mg/dL and 110–125 mg/dL compared with subjects with levels of 70–100 mg/dL (by 11% and 17%, respectively).⁹ However, IFG was not associated with increased risk for ischemic stroke.⁹ Given this weak association between IFG and CVD risk, it is possible that our study was not powered to detect an elevated prevalence of CVD in hypertensive patients with IFG. In addition, our population was relatively young (mean age, 56.5±13.5 years), and this resulted in a relatively low prevalence of CVD, which further limits the statistical power of our study. Indeed, the CIs of the ORs for both CHD and ischemic stroke in patients with IFG were wide (0.62–2.55 and 0.54–3.01, respectively).

Another potential explanation why IFG was not associated with increased prevalence of CVD in our study is that a proportion of patients might have antihypertensive drug-related IFG, which in turn might not be associated with CVD. Indeed, approximately one-half of patients with IFG (47.0%) were being treated with β-blockers, diuretics, or both β-blockers and diuretics. It is well established that both β-blockers and diuretics increase the risk for T2DM.¹⁶ Even though the cross-sectional design of our study does not allow the identification of patients with IFG on β-blockers or diuretics who had developed IFG because of treatment with these agents, it is possible that a considerable number of these subjects had β-blocker- or diuretic-induced IFG. This is supported by the lack of difference in BMI and waist circumference between patients with IFG and those without, suggesting that factors other than obesity (e.g., antihypertensive treatment) resulted in the development of IFG.

It is unclear whether β-blocker-induced IFG increases CVD risk. In the present study, patients with IFG who were on β-blockers had a numerically but not significantly higher prevalence of CHD than patients with serum glucose levels <100 mg/dL. On the other hand, the prevalence of ischemic stroke was similar in patients with IFG receiving β-blockers and patients with serum glucose levels <100 mg/dL. In a prospective observational study in 754 hypertensive patients followed up for 25–28 years, new-onset diabetes during antihypertensive treatment (β-blockers and diuretics in the majority of patients) was associated with increased risk for myocardial infarction and stroke.¹⁷ In another study in 316 hypertensive patients treated with β-blockers or diuretics, those who exhibited an increase in serum glucose levels had increased risk for myocardial infarction.¹⁸ However, neither of these studies evaluated patients treated with β-blockers separately from those treated with diuretics. Diuretics appear to increase the incidence of diabetes by inducing hypokalemia, which in turn impairs insulin secretion.^26,27 On the other hand, β-blockers induce insulin resistance through a reduction in skeletal muscle blood flow and an increase in body weight.^28,29 Given the different pathogenesis of β-blocker- and diuretic-associated diabetes, it is unclear whether they are associated with the same risk for CVD. In addition, there are no studies that evaluated the association between β-blocker-induced IFG and CVD events. In our cross-sectional study, the numerically higher prevalence of CHD in patients with IFG treated with β-blockers might suggest reverse causality (i.e., patients were treated with β-blockers because they had CHD). The comparable prevalence of ischemic stroke in patients with IFG who were on β-blockers and in patients with serum glucose levels <100 mg/dL supports this possibility and argues against a strong association between β-blocker-induced IFG and CVD.

Patients with IFG who were on diuretics had the same prevalence of CHD and ischemic stroke compared with patients with serum glucose levels <100 mg/dL. It is interesting that this lack of difference was observed despite the fact that patients with IFG who were on diuretics were older and had higher serum LDL-C levels than patients with serum glucose levels <100 mg/dL. Previous prospective observational studies reported increased CVD morbidity in hypertensive patients who developed T2DM during antihypertensive treatment.^17
–19 However, these studies did not assess separately the impact of diuretic-induced diabetes on CVD risk. On the other hand, randomized controlled trials did not show an association between diuretic-associated diabetes and CVD events. Indeed, in the Systolic Hypertension in the Elderly Program trial, during a mean follow-up period of 14.3 years, diabetes that developed during the trial in the placebo group was associated with elevated CVD mortality rate, whereas diabetes that developed in patients treated with chlorthalidone did not increase CVD mortality.²⁰ In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, after a mean follow-up of 6.9 years, new-onset diabetes was not associated with adverse CVD outcomes in patients treated with chlorthalidone.³⁰ It is interesting that in the same study, patients who developed diabetes during treatment with either lisinopril or amlodipine had increased CVD morbidity compared with patients who developed diabetes during treatment with chlorthalidone.³⁰ In another post hoc analysis of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, an increase in serum glucose levels was not associated with increased CVD events in patients treated with chlorthalidone.²¹ This lack of association between diuretic-induced diabetes and CVD might be because these patients have a milder increase in serum glucose levels and are less obese than patients with obesity-related T2DM.²⁰ On the other hand, macrovascular complications of T2DM develop over a long period of time, and it is possible that the existing studies did not have an adequately long follow-up.²² Moreover, there are no studies that evaluated the association between diuretic-induced IFG and CVD events. Our findings, with all the limitations inherent to a cross-sectional design, suggest that diuretic-induced IFG is not associated with increased prevalence of CVD, but clearly more studies are needed to assess the clinical implications of diuretic-induced dysglycemia.

Our study has potentially important clinical implications. First, the high prevalence of IFG in hypertensive patients suggests that serum glucose levels should be carefully monitored in this population because of the increased risk for T2DM and the potentially elevated risk for CVD in patients with IFG. Second, because antihypertensive treatment-related IFG does not appear to be associated with increased CVD risk, the choice of antihypertensive medications should be primarily based on their effects on CVD events and not on their effects of glucose metabolism, with the possible exception of patients at high risk for developing T2DM (e.g., obese patients or those with the metabolic syndrome). In the latter patients, β-blockers and diuretics might have to be avoided unless compelling indications for their use are present.

Our study has limitations. The cross-sectional design does not allow the distinction of patients who developed IFG because of antihypertensive treatment from those who already had IFG when started on antihypertensive agents. Furthermore, the cross-sectional design does not allow the distinction of patients who developed CHD due to β-blocker-induced IFG from those who were started on β-blockers because they already had CHD. However, until prospective studies that address the association between antihypertensive treatment-induced IFG and CVD are performed, cross-sectional analyses might provide potentially useful information to guide clinical decisions. Another limitation of our study was that we have no data on the duration of exposure to the different antihypertensive agents. Longer exposure to β-blockers and diuretics is expected to increase more the risk for IFG-related CVD. Indeed, studies that did not show an association between diuretic-induced new-onset diabetes and CVD events^20,21 had shorter follow-up than studies that reported an association (6.9–14.3 and 17.4–28 years, respectively).^17,18 Future prospective studies should address this important point.

In conclusion, IFG is highly prevalent in hypertensive patients but does not appear to be associated with increased prevalence of CVD. Moreover, our findings do not support a elationship between β-blocker- or diuretic-induced IFG and CVD. However, given the high prevalence of IFG in hypertensive patients, further investigation of the impact of antihypertensive treatment-associated IFG and diabetes is required.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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