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Am J Physiol Heart Circ Physiol 292: H608-H613, 2007. First published August 25, 2006; doi:10.1152/ajpheart.00516.2006
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Effects of sulfonylureas on left ventricular mass in type 2 diabetic patients

Tsung-Ming Lee,1 Mei-Shu Lin,2 Chang-Her Tsai,3 Chen-Ling Huang,4 and Nen-Chung Chang5

1Cardiology Section, Department of Medicine, Taipei Medical University and Chi-Mei Medical Center, Tainan; 2Department of Pharmacy, National Taiwan University and Hospital, Taipei; 3Cardiology Section, Department of Surgery, E-DA Hospital and I-Shou University, Kaohsiung; and 4Endocrine Section and 5Cardiology Section, Department of Medicine, Taipei Medical University and Hospital, Taipei, Taiwan

Submitted 20 May 2006 ; accepted in final form 21 August 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Myocardial ATP-sensitive potassium (KATP) channels have been implicated in attenuating cardiac hypertrophy by modulating endothelin-1 concentrations. Sulfonylureas differ in their affinity for cardiac KATP channels and therefore may vary in their effects on left ventricular (LV) mass. We sought to determine the differential effects of sulfonylureas on LV mass in type 2 diabetic patients. All patients had been taking glibenclamide for more than 3 mo before being randomized to either switch to an equipotent dose of gliclazide or continue glibenclamide. A total of consecutive 240 diabetic patients were randomized into glibenclamide, gliclazide, a combination of glibenclamide and nicorandil, or gliclazide and nicorandil for 6 mo. In the gliclazide-treated group, the LV mass index was significantly decreased compared with that in the glibenclamide-treated groups. Nicorandil administration significantly reduced LV mass in glibenclamide-treated patients compared with patients treated with glibenclamide alone. Measurements of endothelin-1 concentrations mirrored the functional status of KATP channel. Multivariate analysis revealed that regression of LV mass was significantly correlated only with the changes in endothelin-1 (P < 0.0001). Our results show that KATP channels may play a pathogenetic role, probably through an endothelin-1-dependent pathway, in diabetes mellitus-related ventricular hypertrophy. Patients treated with gliclazide may have a beneficial effect in attenuating ventricular mass.

adenosine 5'-triphosphate-sensitive potassium channels; diabetes mellitus; glibenclamide; gliclazide; ventricular hypertrophy

INCREASED LEFT VENTRICULAR (LV) mass is a risk factor of cardiac morbidity and mortality not only in patients with essential hypertension but also in the general population (27). The risk increase is independent of other cardiovascular risk factors, including hypertension (7). Previous data revealed that LV mass regression reduced cardiovascular complications (27). Thus LV mass reduction is widely accepted as a desirable treatment goal.

Cardiac hypertrophy is a complex process involving numerous signaling pathways. Pharmacological therapies, such as angiotensin-converting enzyme inhibitors and beta-blockers, have been used to improve cardiac hypertrophy (28). Previous studies have shown that LV remodeling, a process of ventricular hypertrophy, is improved by nicorandil treatment after myocardial infarction (26), implying that myocardial ATP-sensitive potassium (KATP) channels may play a role in ventricular hypertrophy. Recently, our group (18) showed a direct relation between the activation of myocardial KATP channels and ventricular remodeling by administering KATP channel antagonists in hyperlipidemic rabbits. Activation of KATP channels has been shown to attenuate cardiac hypertrophy by inhibition of endothelin-1 (ET-1) (33), a key mediator of protein synthesis for hypertrophic changes.

Previous studies have shown that diabetic patients have a substantially higher LV mass index than nondiabetic patients (6). The mechanisms involved remain unclear. Sulfonylureas represent the most commonly prescribed pharmacological treatment for type 2 diabetic patients. Sulfonylurea drugs stimulate insulin secretion by closing KATP channels in pancreatic beta-cell membrane. Unfortunately, KATP channels also occur in the cardiovascular system, where they are thought to play an important role in LV hypertrophy. Thus the use of sulfonylurea drugs may be harmful. Differential response of sulfonylurea drugs was determined using the sulfonylurea receptor (SUR) isoform because multiple regions of SUR contribute to coupling antagonist-occupied site(s) with the inwardly rectifying potassium channel (KIR) gating machinery (3). Gliclazide is pharmacologically distinct from glibenclamide because of differences in SUR receptor-binding properties (9) that could result in a reduced binding to cardiomyocyte KATP channels as reflected in the lower KATP channel current inhibition activity (16). Gliclazide is a sulfonylurea with high affinity and strong selectivity for pancreatic SUR 1 but has no significant action on cardiac SUR 2A (9).

To our knowledge, no studies have assessed whether therapeutic doses of sulfonylureas in diabetic patients may modulate LV mass. The goal of the present study was to determine whether the chronic use of sulfonylurea drugs alters ventricular mass and to assess whether an agonist of KATP channels, nicorandil, can mimic the beneficial effects of attenuated ventricular hypertrophy in diabetic patients.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects. The study was conducted prospectively. The protocol consisted of a 4-wk screening period and a 6-mo treatment period (Fig. 1). Patients ages 40–80 yr were eligible if they met the National Diabetes Data Group definition for type 2 diabetes, with endogenous insulin production (fasting C-peptide concentration ≥0.8 ng/ml at screening) and with glibenclamide as one of the hypoglycemic regimen. Individuals with impaired glucose tolerance were not considered in this study. Impaired glucose tolerance is determined by measuring plasma glucose levels 2 h after glucose loading in the oral glucose tolerance test. Impaired glucose tolerance is associated with increased risk of developing type 2 diabetes. To date, several clinical trials have found that life style modification is the most efficacious strategy to prevent progression to type 2 diabetes. Alternative treatments include pharmacotherapy with metformin or acarbose, both of which have been demonstrated to decrease the development of type 2 diabetes (25). Other drugs, such as those indicated to treat other parameters of the metabolic syndrome, also may be useful. Because glibenclamide is not recommended for patients with impaired glucose tolerance, such patients were excluded from the study. All patients were on stable doses of oral hypoglycemic agents and other medications for at least 3 mo before undergoing screening echocardiography and randomization.


Figure 1
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  		Fig. 1. Randomization protocol. For exclusion criteria, see text.

 
Patients were excluded from participation if they had clinical significant renal disease with plasma creatinine level >1.8 mg/dl, severe valvular heart disease, atrial fibrillation, uncontrolled blood pressure >180/110 mmHg, or symptoms or signs or history of cardiovascular disease. Patients with a definite indication for long-term insulin therapy were not eligible for inclusion. We defined the patients as having a definite indication for long-term insulin therapy if the glycosated hemoglobin (HbA1c) was >9.5% on dual therapy including glibenclamide at a maximal dose of 20 mg, which was modified from a previous definition (29). Whereas patients taking angiotensin converting enzyme inhibitors, angiotensin II receptors antagonists, and lipid-lowering agents were not excluded from the study, doses were not to be changed during the study unless deemed medically appropriate.

During a 4-wk run-in period, we confirmed whether the patients were eligible for the study. Exclusion criteria were rechecked during the run-in period. Eligible patients were randomly assigned to keep original glibenclamide or to shift to gliclazide, which was titrated at the discretion of the investigator and held constant for the duration of the study period. We encouraged the investigators to achieve the goal of the American Diabetes Association’s recommended targets for glycemic control including a preprandial blood glucose level of 80–120 mg/dl, a bedtime blood glucose level of 100–140 mg/dl, and an HbA1c level of <7% (2). Five milligrams of glibenclamide are equivalent to 80 mg of gliclazide in terms of glycemic control. To further confirm whether activation of KATP channels is mandatory for LV mass, we assessed diabetic patients treated with nicorandil. Nicorandil was orally administered at a dose of 15 mg/day, which has been shown to activate KATP channels (22). Consecutive patients were enrolled and randomized into four treatment groups: those treated with glibenclamide, those treated with gliclazide, those treated with glibenclamide and nicorandil, and those treated with gliclazide and nicorandil (Fig. 1). Weight and height were measured using standard techniques. Body mass index was calculated as body weight divided by height squared. Hypertension was considered present when arterial blood pressure was persistently 140/90 mmHg or when patients received blood pressure-lowering drugs. More detailed information concerning the population studied is given in Table 1. Patients gave written informed consent to participate in this study, which was approved by the institutional ethics committee.


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  		Table 1. Clinical characteristics and lipid profiles of diabetic patients and control subjects

 
Echocardiographic assessment. Echocardiographic determinations were carried out by experienced investigators (N.-C. Chang, T.-M. Lee) blinded to clinical and laboratory data. The primary study end point was the change in LV mass index between baseline and 6 mo of therapy. In addition, the study assessed changes from baseline to the end of the study (6 mo) in LV systolic function. Study patients received two-dimensional echocardiography by a single examination at baseline and at 6-mo follow-up, respectively. A commercially available system (Hewlett-Packard Sonos 5500, Andover, MA) was used. Heart rate was determined from a continuous electrocardiographic tracing. Baseline heart rate and systemic arterial pressure were measured. The LV end-diastolic dimension (EDD), end-systolic dimension (ESD), ventricular septum thickness (VS), posterior wall thickness (PW), and LV ejection fraction were measured as described previously (19). Echocardiographic LV mass was determined using the corrected formula proposed by Penn (5):

Formula
LV mass was indexed by body surface area (g/m2). Measurements were averaged for three consecutive beats. Video images were recorded for off-line analysis.

Biochemical analysis. Blood samples were taken after an 8-h overnight fasting at baseline and after 6 mo of treatment. It has been shown that activation of KATP channels is associated with attenuated ET-1 concentrations (33). To confirm the downstream pathways of KATP channel, we collected plasma samples for ET-1 measurements and extracted as previously described (20). Samples were immediately centrifuges at 3,000 g for 10 min, and the plasmas were stored at –70°C until further analysis. ET-1 was measured by immunoassay (R&D System, Minneapolis, MN). The detection limit was 1 pg/ml for ET-1. There was <1% cross-reactivity with big-endothelin 22–38. Intra-assay and interassay coefficients of variation were 4.5 and 6.6%, respectively.

Fasting plasma glucose, HbA1c, insulin, C-peptide, and creatinine constituted the glycemic laboratory parameters. Plasma concentrations of total, high-density lipoprotein cholesterol, and triglycerides were measured using enzymatic methods as previously described (1, 23). Low-density lipoprotein cholesterol was calculated using the Friedewald equation (32). All blood specimens were collected at the participating sites and shipped to the central laboratory. Analyses were duplicated at a single time point, and results are expressed as mean values.

Reproducibility of echocardiographic measurements. To check interobserver variability of LV mass, independent and duplicate determinations were made by a second experienced investigator (T.-M. Lee) on a subgroup of 50 echocardiograms. The coefficient of variability was calculated with the formula: {delta} = {Sigma} (X1 – X2)2/(2n – 1). The coefficient of variability ({delta}/LV mass) was 0.9% (1.6 g) for duplicate LV mass measurements and 1.2% (1.1 g/m2) for LV mass index. The coefficient of variability in intraobserver variability obtained by randomly inserting 30 echocardiograms was 0.7% (1.3 g) for LV mass and 0.8% (0.8 g/m2) for LV mass index.

Statistical analysis. All data were analyzed using Excel (Microsoft, Seattle, WA) software loaded with SPSS software (SPSS, Chicago, IL). The continuous variables were expressed as means ± SD. Differences in baseline characteristics, hemodynamics variables, and LV mass among groups were determined by ANOVA. Baseline and 6-mo follow-up data were analyzed using the paired Student’s t-test. For the identification of independent predictors of LV mass index, the change in LV mass index was used as the dependent variable, with changes in pulse pressure, age, and ET-1 as potential independent variables. Relationships among the changes were studied using Spearman correlation and multiple linear regression analysis. All study outcomes were analyzed only in patients who completed the 6-mo trial. A two-way ANOVA was used to search for possible effects of nicorandil and glibenclamide on the measurements of LV mass, and if an F value was found to be significant, a two-tailed Student’s t-test for paired observation with Bonferroni’s correction was used to test differences. For the categorical parameters, the differences were compared by {chi}2 test and Fisher’s exact test if case number was <5. A P value <0.05 was considered statistically significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
A total of 312 patients met the criteria for inclusion, and 72 of these patients (23%) met one or more criteria for exclusion. A total of 240 consecutive patients were randomized into four study groups. There were a total of 219 evaluable and completed patients. Table 1 presents the baseline and demographic characteristics of patients in each group. There were no significant differences at baseline among the groups. Blood glucose and blood pressure were similar among the four diabetic groups throughout the study (Table 2). The effects of glibenclamide and gliclazide on insulin secretion were very similar in patients with type 2 diabetes, consistent with previous studies (31).


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  		Table 2. Hemodynamics, blood glucose, insulin, C-peptide, and BMI at baseline and 6 mo of therapy

 
Echocardiographic measurements. At baseline, all groups had similar LV mass. After 6 mo, there was no significant change in LV mass index in the glibenclamide group (Table 3). In contrast to glibenclamide treatment, gliclazide had a significantly attenuated LV mass index (17%, P < 0.0001) during the follow-up compared with baseline despite an equivalent control in glycemia. There was a significantly higher LV mass index between the glibenclamide- and the gliclazide-treated groups (142 ± 38 vs. 106 ± 24 g/m2 in the gliclazide group, P < 0.0001) after 6 mo. The reduction of LV mass index was due to reduction of LV ESD (28.1 ± 4.5 mm at baseline vs. 27.0 ± 4.4 mm at 6 mo, P = 0.0001) and LV EDD (43.6 ± 4.3 mm at baseline vs. 42.2 ± 4.6 mm at 6 mo, P < 0.0001). Nicorandil administration significantly attenuated LV mass index in the glibenclamide group compared with treatment with glibenclamide alone. There was no significant difference of LV mass index regression during the follow-up in groups treated with either gliclazide or gliclazide plus nicorandil (17 ± 14 vs. 15 ± 12%, P = not significant).


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  		Table 3. Echocardiographic parameters and ET-1 levels at baseline and 6 mo of therapy

 
ET-1. There were similar baseline ET-1 levels among the four groups (Table 3). ET-1 levels were significantly reduced in gliclazide-treated patients compared with those in glibenclamide-treated patients, whose ET-1 levels remained stable throughout the study. Patients with additional nicorandil in treatment had a significant reduction of ET-1 compared with those treated with glibenclamide alone.

Correlation. Multiple linear regression models were assessed for each dependent variable listed in Table 4. A robust inverse correlation was found between the changes of ET-1 and LV mass index [change in LV mass index (%) = 0.63 x change in ET-1 (%) + 0.29, r = 0.50, P < 0.0001, Fig. 2], suggesting that LV mass index increases as the severity of ET-1 increases.


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  		Table 4. Correlates of percentage differences in LV mass index

 

Figure 2
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  		Fig. 2. Correlation of the change (%) between left ventricular mass index (LVMI) and endothelin-1 (ET-1) in the diabetic patients (r = 0.50, P < 0.0001, n = 219). A greater increase of ET-1 release was associated with a greater increase of LVMI. Glib, glibenclamide; Glic, gliclazide; Nic, nicorandil.

 
To identify determinants of decrease in LV mass index, we implemented multivariate analysis (Table 5). Multivariate regression analysis was performed with LV mass index as dependent variable and age, changes in hemodynamics, and ET-1 as independent variables. The ET-1 was a factor that was significantly related to long-term improvement in LV mass index (beta = 0.495, P < 0.0001, adjusted R2 = 0.253).


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  		Table 5. Multivariate analysis of independent factors for LV mass index

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study showed for the first time that the use of sulfonylurea drugs has effects on ventricular mass, which was associated with an ET-1-dependent pathway. Compared with glibenclamide, a significant decrease in LV mass index was observed in the gliclazide group after 6 mo of treatment. We found differences among classes of sulfonylureas on LV mass that made grouping as a homogeneous class inappropriate without stratifying on the basis of blocking cardiac KATP channels.

Our conclusions are supported by the following observations. 1) Gliclazide was associated with an attenuated LV mass index, which was not observed with glibenclamide. Relieving cardiac KATP channel blockade by shifting glibenclamide to gliclazide causes significant attenuation of LV mass, which suggested a basal modulation of LV mass by cardiac KATP channels. The effect of glibenclamide on LV mass was improved by treatment with nicorandil, further confirming the predominant role of KATP channels in this phenomenon. The observation was consistent with previous findings showing glibenclamide with much less tissue selectivity, because it blocks KATP channel in beta-cells and cardiac muscle (9, 16). Our data are compatible with previous studies by our group showing a pathogenetic role of KATP channels in ventricular hypertrophy induced by hypercholesterolemia (18).

2) The beneficial effects of gliclazide on attenuated LV mass might be associated with reduced ET-1 levels independent of glycemic changes. Patients in whom nicorandil was coadministered had significant reductions of ET-1 compared with those treated with glibenclamide alone. Our findings were consistent with those of Xue et al. (34), showing that chronic treatment with a KATP channel agonist (iptakalim) reduces circulation ET-1 concentrations. Furthermore, this result was consistent with the notion that activation of KATP channels attenuated cardiac hypertrophy by inhibition of ET-1 (33).

In this study, we demonstrated a significant reduction of LV mass in gliclazide-treated diabetic hearts. The mechanisms by which gliclazide affected LV mass remained undefined. However, several factors can be excluded. 1) Hemodynamics: drugs neither exerted hemodynamic effects nor were associated with a change in body weight. Although nicorandil is a vasodilator, the beneficial effect of nicorandil was achieved without clinically important changes in heart rate or blood pressure. The result was consistent with the IONA results, showing that no decrease in blood pressure was observed when the chronic use of nicorandil was administered at the dose of 20–40 mg/day (12).

2) Differences in insulin concentrations: although increased insulin levels have been shown to increase LV mass (11), the insulin levels cannot be a confounding factor of LV mass. There were similar insulin levels among the four groups throughout the study.

3) Differences in glucose concentrations: LV hypertrophy might develop in diabetic patients as a result of higher glucose levels, which independently stimulated LV growth (24). However, when nicorandil was administered in diabetic patients, the LV mass improved without significant changes in blood glucose levels, suggesting that factors other than glucose might contribute to the pathogenesis of LV mass reduction in diabetic patients. Our results were consistent with previous findings of Hata et al. (10), showing that nicorandil administration did not worsen glucose control in diabetic patients.

Other mechanisms. The present study suggests that the mechanisms of gliclazide-induced cardioprotection may be related to nonblockade of myocardial KATP channels; however, based on the correlation shown in Table 5, ET-1 levels explain only 25% of the variation in LV mass. Therefore, gliclazide-induced attenuated LV mass cannot be attributed solely to KATP channel-related ET-1 levels, which stresses the importance of other factors. First, increased production of free radicals may induce cardiac hypertrophy via activation of mitogen-activated protein kinases (30). Blockade of free radicals alleviated the development of cardiac hypertrophy (30). The ability of gliclazide to lower oxidative stress in diabetic patients is not shared by glibenclamide (14). The antioxidant effects of gliclazide may attenuate ventricular mass. Furthermore, nicorandil possesses anti-free radical characteristics, since the nicotinamide moiety of its molecular structure is a known hydroxyl radical scavenger and an inhibitory effect on superoxide anion production (21). Thus the groups treated with nicorandil may attenuate ventricular mass by its antioxidant action. Second, blunting by nicorandil of antihypertropic effect also may result from an increase of nitric oxide activity. The additional effect of nicorandil on top of glibenclamide could be mediated by its nitric oxide donor activity. Because glibenclamide blocks the KATP channel opening properties of nicorandil in vitro (13) without affecting its nitric oxide properties, this additional action of nicorandil on ventricular mass should be considered as a possible explanation for its beneficial effect in glibenclamide-treated patients. However, the significant correlation was observed between ventricular mass and ET-1, implying a pivotal role of KATP channel-related ET-1 in this phenomenon.

Clinical implication. Our results are consistent with our previous studies showing that impairment of myocardial KATP channels is associated with ventricular hypertrophy (34). Our findings have identified KATP channel as a suitable antihypertrophic strategy, particularly in the diabetic myocardium, where KATP channel-dependent mechanisms are impaired by the use of sulfonylureas. Changes in the KATP channel abundance have provided the scenario of treating the diabetic myocardium with the KATP channel openers described in this study.

The extent to which sulfonylureas contribute to the increased risk for cardiovascular disease in diabetes has been debated, partly because sulfonylureas are not a homogeneous group of drugs in terms of their tissue specificity and their effects on cardiac structure. Our results reflect different effects of glibenclamide and gliclazide treatment on LV mass in type 2 diabetic patients. Like ischemic animals, diabetics seem to be much more cardiovascularly sensitive to sulfonylureas (17). Blockade of myocardial KATP channels with glibenclamide at therapeutic doses is associated with impaired reduction of LV mass, thereby contributing to increased mortality. It seems likely that the high selectivity for pancreatic beta-cell KATP channels over those of cardiovascular tissues is a desirable property for sulfonylureas to be used in type 2 diabetes. Our current data add a further piece of information toward explaining the mechanisms underlying this benefit of gliclazide.

Study limitations. There are some limitations in the present study that have to be acknowledged. First, the reliability of echocardiographic measurement of LV mass is substantially important. Gottdiener et al. (8) have shown that the temporal variability of echocardiography for measurement of LV mass precludes its use to measure changes in mass of the magnitude likely to occur with therapy. However, our results have demonstrated an acceptable reliability of repeated measurements of LV mass for identification of clear-cut LV mass in terms of inter- and intra-observer variability. Indeed, our results were compatible with the findings of de Simone et al. (4), showing that M-mode echocardiographic measurement of LV mass demonstrated an acceptable reproducibility for assisting in the stratification of risk in single patients. Besides, although glibenclamide is an antagonist of KATP channels, there are many potential nonspecific targets, including the inhibition of Na+ channels and the opening of Ca2+ channels (15). These alternative effects could confound the interpretation of the present study. However, it seems unlikely, because nicorandil significantly improved the effect of glibenclamide on LV mass.

In conclusion, our results show that KATP channels may play a pathogenetic role in diabetes mellitus-related ventricular hypertrophy. Given that LV mass reduction is accepted as a treatment goal, attenuation of LV mass in gliclazide-treated patients may have a potential beneficial effect, although we did not address the effect of attenuated LV mass on patient outcome. Our findings that different effects of short-term sulfonylurea drugs on LV mass should pave the way for additional large-scale clinical trial aimed at evaluating long-term clinical benefits of gliclazide therapy in type 2 diabetes mellitus.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by the National Science Council, Taiwan, Republic of China (NSC94-2314-B-384-001), and Chi-Mei Medical Center Grants CMFHT9201, CMFHR9502, CMFHR9506, and Chi-TMU9501.


   FOOTNOTES
 

Address for reprint requests and other correspondence: N.-C. Chang, Cardiology Section, Dept. of Medicine, Taipei Medical Univ. and Hospital, 252 Wu-Hsing St., Taipei 110, Taiwan (e-mail: ncchang{at}tmu.edu.tw)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
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