Hypertension and diabetes commonly occur

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1 O r i g i n a l P a p e r Instant CME Credit Treatment With Metoprolol Succinate, a Selective Beta Adrenergic Blocker, Lowers Blood Pressure Without Altering Insulin Sensitivity in Diabetic Patients Bonita Falkner, MD; 1 Harvey Kushner, PhD 2 Insulin resistance is a risk factor for cardiovascular disease. Therapies to lower blood pressure should not decrease insulin sensitivity, especially among high-risk patients such as diabetics. This study examined the effect of the b1-selective adrenergic receptor blocking agent extendedrelease metoprolol succinate (ER metoprolol) on insulin sensitivity in type 2 diabetic patients with suboptimal blood pressure control. Diabetic patients with average blood pressure levels >130/85 mm Hg despite antihypertensive therapy had insulin sensitivity quantified by insulin clamp. ER metoprolol was then added to their ongoing therapy. Following 12 weeks of ER metoprolol plus other therapy, the insulin clamp study was repeated. There were no significant changes in measures of insulin sensitivity, plasma lipids, or hemoglobin A 1c with use of ER metoprolol. When b-blocker therapy is considered, it appears that this agent can be used to treat hypertension without adverse effects on insulin sensitivity From the Department of Medicine, Division of Nephrology, Thomas Jefferson University, Philadelphia, PA; 1 BioMedical Computer Research Institute, Inc, Philadelphia, PA 2 Address for correspondence: Bonita Falkner, MD, Department of Medicine, Thomas Jefferson University, 833 Chestnut Street, Suite 700, Philadelphia, PA Bonita.Falkner@jefferson.edu Manuscript received July 11, 2007; revised September 11, 2007; accepted September 12, ID: 7458 in patients with type 2 diabetes, at least over the period of time treated. (J Clin Hypertens (Greenwich). 2008;10:51 57) 2008 Le Jacq Hypertension and diabetes commonly occur together in individual patients; together, these 2 conditions markedly increase the risk of cardiovascular events. 1 Because of the heightened risk of morbid events among diabetics with hypertension, the recommended therapeutic blood pressure goal for antihypertensive treatment in diabetic patients is <130/80 mm Hg. 2 This recommended treatment goal is achieved in only about 36% of adult diabetic patients. 3 To achieve optimal blood pressure control in high-risk patients, especially diabetic patients, a combination of at least 2 or 3 antihypertensive agents is usually required. Beta adrenergic blocking agents (b-blockers) improve outcomes in hypertensive patients with high-risk complications such as heart failure, myocardial infarction, and diabetes. b-blockers improve outcomes to a greater extent in diabetic patients with a history of myocardial infarction or coronary artery disease than in those with similar cardiac conditions without diabetes. 4 Patients with type 2 diabetes usually have marked insulin resistance. Insulin resistance with concurrent hyperinsulinemia promotes an atherogenic profile and raises the risk of advancing atherosclerotic injury. 5 Clinical concerns that may limit the use of b-blockers in diabetic patients with hypertension involve the potential for adverse metabolic effects from b-blockers, including worsening of VOL. 10 NO. 1 January 2008 THE Journal of Clinical Hypertension 51 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.

2 dyslipidemia and insulin resistance. Therefore, the established cardiovascular benefits of b-blocker therapy in high-risk patients must be balanced against the possible risks of an adverse metabolic effect, which may attenuate some benefits. b-blockers have been reported to impair insulin sensitivity or contribute to insulin resistance, 6 adversely affect lipid metabolism, 7 and increase the risk of new-onset diabetes. 8 Recent clinical investigations, however, have failed to show adverse metabolic effects of certain b-blockers. The combined b-/a-blocker carvedilol was compared with the short-acting selective b-blocker metoprolol tartrate in a large clinical trial in hypertensive diabetic persons. Results of the trial indicated that carvedilol had a neutral effect on lipids and hemoglobin A 1c (HbA 1c ) and also reported a slight improvement in insulin sensitivity, estimated by the homeostasis model assessment (HOMA) equation when compared with metoprolol tartrate. 9 In a previous study, however, that examined the effect of the long-acting selective b-blocker metoprolol succinate in nondiabetic hypertensive patients on insulin sensitivity, quantified by the insulin clamp procedure, no adverse effects on insulin sensitivity or on plasma lipids were detected. 10 The purpose of this study was to examine the metabolic effect of the b1-selective adrenergic receptor blocking agent extended-release metoprolol succinate (ER metoprolol) in patients with type 2 diabetes mellitus and to determine whether this b-blocking drug has a detectable or clinically meaningful effect on insulin sensitivity in diabetic patients with hypertension, specifically. This study utilized the euglycemic hyperinsulinemic clamp procedure to rigorously quantify insulin sensitivity. Methods Study Plan This study was conducted in adult men and women with type 2 diabetes mellitus and suboptimal blood pressure control. All patients had confirmed diabetes and were receiving antidiabetic therapy. Diabetic patients who also had hypertension were screened for participation in the study. Patients who had repeated blood pressure measurements of >130/85 mm Hg while receiving antihypertensive medications, excluding b-blockers, were enrolled in the study. Patients were excluded if they had asthma, heart failure, or reduced renal function (serum creatinine level >1.4 mg/dl) or if the hypertension was secondary to an endocrine or renal vascular disorder. Patients were also excluded if 3 or more antihypertensive medications were required for blood pressure control or if the screening blood pressure level was 180/120 mm Hg. At the enrollment visit, written informed consent was obtained on a protocol that was approved by the institutional review board of Thomas Jefferson University. Screening measures for enrollment included a complete blood cell count, blood chemistry panel, HbA 1c, fasting plasma lipids, and electrocardiography. Blood pressure was measured by auscultation and a mercury column instrument, with the patient rested and in the seated position. Blood pressure cuff sizes that were appropriate for the upper arm were used. 11 Anthropometric measurements, including weight, height, and skinfold thickness were obtained to compute percent body fat and fat-free mass (FFM). 12,13 The study was designed to reflect an accepted treatment plan for diabetic patients with hypertension. All patients were receiving an angiotensinconverting enzyme inhibitor or an angiotensin receptor blocker and a diuretic as part of their ongoing treatment before enrollment. These medications were continued throughout the study at the patient s usual dosage. Patients were enrolled if their average blood pressure level on antihypertensive therapy was >130/85 mm Hg. Each enrolled patient with diabetes and suboptimal blood pressure control underwent an insulin clamp procedure to quantify insulin sensitivity. After the insulin clamp procedure, the patient continued his/ her dosage of antihypertensive medication, and ER metoprolol was added with a beginning dosage of 50 mg/d. Participants were instructed to continue their usual diet and level of physical activity and to attempt to maintain current body weight until completion of their participation in the study. ER metoprolol was titrated upward every 2 weeks to a dosage that lowered blood pressure to <130/85 mm Hg. The maximum dosage of ER metoprolol was 200 mg/d. Following 12 weeks of added ER metoprolol therapy, the insulin clamp procedure was repeated. The complete blood cell count, blood chemistries, HbA 1c measurement, and fasting lipid panel were also repeated on treatment with ER metoprolol. Insulin Clamp Procedure The euglycemic hyperinsulinemic clamp is a method to measure insulin-stimulated glucose utilization (or disappearance) under steady-state conditions. With the clamp procedure, plasma insulin concentration is elevated to a predetermined level by a primed constant infusion of insulin. During hyperinsulinemia, euglycemia (fasting plasma 52 THE Journal of Clinical Hypertension VOL. 10 NO. 1 January 2008 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.

3 glucose concentration) is maintained by an infusion of exogenous glucose. The glucose provided by the exogenous infusion is utilized in insulin sensitive tissues, and plasma glucose concentration is maintained at the fasting level. The method for the insulin clamp procedure is as follows. The patient reports to the laboratory after a 10-hour overnight fast, during which time water may be consumed as desired. A rest period (20 minutes) occurs after insertion of a plastic catheter in a distal portion of the arm for all infusions. A small (22-gauge) catheter is inserted in a dorsal vein of the opposite hand for sample withdrawal. The hand with the sampling catheter is kept warm to ensure arterialization. Prior to the onset of euglycemic hyperinsulinemia, 2 samples are withdrawn for determination of fasting plasma glucose (basal glucose) and fasting plasma insulin values. Among diabetic patients who have an elevated fasting glucose level, insulin is given initially to lower the plasma glucose level to 100 mg/dl before beginning the clamp procedure. Hyperinsulinemia is established with a primed constant infusion of insulin, using the method of Rizza and colleagues 14 to calculate the priming dose and infusion rate. Insulin (regular human insulin; Novolin, Novo Nordisk, Clayton, NC) is administered at the concentration of 1000 miu/ml in normal saline. Hyperinsulinemia is maintained for 120 minutes, during which time euglycemia is achieved using a variable infusion of 20% dextrose in water (Abbott Laboratory, Abbott Park, IL). Following the onset of the insulin infusion, plasma glucose is measured every 10 minutes. From 60 through 120 minutes of hyperinsulinemia, an additional sample of plasma is obtained every 10 minutes and frozen until assayed for insulin at a later time. A negative feedback equation, 15 programmed on a PC, is used to determine the glucose infusion rate. Use of the feedback equation prevents wide swings in the glucose infusion rate and facilitates a more stable glucose clamp period. To avoid investigator bias in setting the glucose infusion rates, the procedure is conducted by research nurses who are trained to achieve the target plasma glucose concentration. With this method, we have demonstrated that in our laboratory, the coefficient of variation for plasma glucose concentration is <5.0% during the final 60 minutes of the procedure. 16 Insulin sensitivity (M) is calculated as the mean glucose infusion rate during the final 60 minutes of euglycemic hyperinsulinemia. Both glucose and insulin solutions are infused with a syringe pump (Harvard Model 22; Harvard Apparatus, Holliston, MA). Plasma glucose concentration is analyzed by glucose oxidase Table I. Diabetic Participants With Hypertension Male/female 14/14 Age, years (range) 51.4±9.6 ( ) Prestudy weight, kg (range) 98.0±19.3 ( ) Poststudy weight, kg 97.4±20.2 Prestudy BMI, kg/m 2 (range) 33.9±6.5 ( ) Blood pressure, mm Hg During usual treatment SBP 141±11 DBP 88±6 ER metoprolol + usual treatment SBP a 132±10 DBP b 79±9 Values are mean ± SD. a P=.003; b P<.001; P values reflect systolic blood pressure (SBP) and diastolic blood pressure (DBP) difference between usual treatment and extendedrelease metoprolol succinate (ER metoprolol) + usual treatment. Abbreviation: BMI, body mass index. technique (YS Model 27; Glucostat, Yellow Springs, OH). Plasma insulin concentration is analyzed by solid phase radioimmunoassay (Coata-Count; Diagnostic Products Corp, Los Angeles, CA). Coefficients of variations for interassay and intraassay variability for glucose and insulin assays in our laboratory are typically <5%. The glucose infusion rate to maintain euglycemia is the quantitative measure of insulin-stimulated glucose metabolism, M (mg/kg/min). Despite the same insulin infusion rate, there will be individual variation in the insulin concentration during steady-state hyperinsulinemia, especially among diabetic patients, due to variable fasting insulin concentration and insulin clearance rate. Therefore M is adjusted for the clamp steady-state insulin concentration (I c ) to derive an insulin sensitivity index, M/I c. To adjust for adiposity and ascertain insulin-mediated glucose uptake in insulin-sensitive tissue, anthropometric measures are used to calculate FFM. 12,13 The measured glucose uptake is then computed and expressed as M' in mg/kg FFM/min. M' is also adjusted for steady-state insulin concentration to achieve an insulin sensitivity index based on FFM (M'/I c ). An increase in M/I c or M'/ I c (determined by an increase in the glucose infusion rate) indicates an increase in insulin sensitivity, whereas a decrease in these measures indicates greater insulin resistance. Data Analysis The primary end point in this study was change in the insulin clamp measure of insulin sensitivity, M/I c. Secondary end points were change in VOL. 10 NO. 1 January 2008 THE Journal of Clinical Hypertension 53 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.

4 Table II. Insulin Sensitivity Determined by Insulin Clamp Before and During ER Metoprolol Therapy Usual Treatment Usual Treatment + ER Metoprolol P Value a Glucose (basal), mg/dl 98.5± ± Glucose (clamp), mg/dl 96.0± ± Insulin (basal), mu/ml 12.1± ± Insulin (clamp) (I c ), mu/ml 103.2± ± M, mg/kg/min 4.60± ± M/I c 6.03± ± M', mg/kg FFM/min 7.14± ± M'/I c 9.18± ± Values are mean ± SD. a No significant difference by paired analysis. Abbreviations: ER metoprolol, extended-release metoprolol succinate; FFM, fat-free mass; Ic, plasma insulin concentration during steady-state hyperinsulinemia; M, insulin-mediated glucose uptake; M/I c, glucose uptake adjusted for level of steady state hyperinsulinemia; M', glucose uptake adjusted for adiposity; M'/I c, glucose uptake adjusted for adiposity and steady state hyperinsulinemia. M, M', and M'/I c, HbA 1c, indirect estimates of insulin sensitivity, 17,18 and plasma lipid concentrations. Previous data from repeat insulin clamp measures within participants were used to develop a power analysis to estimate sample size for a single-treatment open-label study. 19,20 Data from these studies indicated a mean percent change in M of 19% with a standard deviation (SD) of 38%. Based on a power analysis for a one-tailed paired t test of equivalence with power of 80%, an equivalence limit of 30%, an expected difference of 15% (which is near the 19%), and a standard deviation of 30%, 27 participants would be needed. The effect size was 0.50 or 50%. Comparisons between prestudy and poststudy data were performed using paired t tests. P values <.05 were considered statistically significant. All values are presented as mean ± SD. Analyses were performed using SAS (version 8.2, SAS institute, Cary, NC). Results A total of 41 participants were screened and enrolled in this study. Of these, 6 patients were excluded because of abnormal laboratory results; 7 patients were subsequently discontinued because of symptoms in 1 patient and noncompliance in 6 patients. No patients were withdrawn during treatment for insufficient blood pressure control. Thus, the final study sample consisted of 28 diabetic hypertensive patients who had insulin sensitivity measured by the insulin clamp procedure while receiving their usual therapy and again following 12 weeks of added ER metoprolol. This sample included 14 women and 14 men. Table I provides mean values for age, body mass index (BMI), and blood pressure levels at baseline, on usual therapy, and following 12 weeks of the b-blocker therapy added to usual treatment. Following titration of ER metoprolol, the dosage was 50 mg/d in 46% (n=13) of the sample, 100 mg/d in 40% (n=11), and 200 mg/d in 14% (n=4). Compared with usual treatment with an reninangiotensin-aldosterone system (RAAS) inhibitor and a diuretic, there was a statistically significant decrease in both systolic (P=.003) and diastolic (P<.001) blood pressure with the b-blocker added to other antihypertensive drug treatment. There was no significant change in weight or BMI during the 12 weeks of treatment. Compliance with medication regimen was ascertained by direct questioning and pill count. The mean calculated compliance by study visit ranged from 84.0±29.1% to 89.5±14.6% for the study sample of 28 participants. The measures of insulin sensitivity derived from the insulin clamp procedure are presented in Table II. The clamp glucose concentration was nearly identical to basal glucose concentration at each clamp. The posttreatment insulin clamp (usual antihypertensive medication + ER metoprolol) basal and clamp glucose concentrations are also nearly identical to the pretreatment insulin clamp (usual antihypertensive medication only), indicating that the conduct of the insulin clamp procedures were identical before and during the b-blocker therapy. Using the prespecified criteria for the absence of a meaningful change from baseline, there was no statistically or clinically significant difference between the pretreatment and posttreatment values in any of the clamp-derived measures of insulin sensitivity, including M, M', M/I c, and M'/I c. The data were also analyzed as percent change in insulin sensitivity with ER metoprolol treatment (data not shown), and no significant effect was detected. The insulin sensitivity index before and during treatment is depicted for each case in the Figure. Values <7.5 mg/kg*min 100 are indicative of insulin resistance. Most participants showed little change in the insulin sensitivity index following the addition of ER metoprolol therapy. Three patients demonstrated 54 THE Journal of Clinical Hypertension VOL. 10 NO. 1 January 2008 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.

5 Table III. Metabolic Measures Before and During ER Metoprolol Treatment Usual Treatment Usual Treatment + ER Metoprolol P Value HOMA 2.96± ± QUICKI 0.15± ± Hemoglobin A 1c 7.5± ± Cholesterol, mg/dl 177±50 180± HDL, mg/dl 44±12 43± LDL, mg/dl 106±35 112± Triglycerides, mg/dl 153± ± Values are mean ± SD. Abbreviation: ER metoprolol, extended-release metoprolol succinate; HDL, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; LDL, low-density lipoprotein cholesterol; QUICKI, quantitative insulin sensitivity check index. an increase in M/I from <7.5 to >7.5 mg/kg*min 100, indicating greater insulin sensitivity. Three participants demonstrated a decrease in insulin sensitivity. Drug dosage had no effect on the decrease, as 2 patients were receiving 100 mg/d and 1 patient was receiving 50 mg/d. The 4 participants receiving 200 mg/d had no change in insulin sensitivity. Using both Spearman and Pearson correlation analyses, there was no detectable effect of weight change on change in any of the measures of insulin sensitivity. As shown in Table II, there were no significant differences before and following treatment in fasting plasma glucose concentration or fasting plasma insulin concentration. The fasting glucose and insulin values were used to compute indirect estimates of insulin sensitivity, including HOMA 17 and the quantitative insulin sensitivity check index (QUICKI). 18 As shown in Table III, there were also no changes in these estimates of insulin sensitivity following ER metoprolol treatment. Table III also provides data on assessments of HbA 1c and plasma lipids. There was no significant change in values of HbA 1c, and there were no statistically significant changes in plasma lipids following the addition of the b-blocker to usual treatment. Of the entire sample of 28 diabetic patients, 11 were receiving therapy for lipid reduction on enrollment and continued to take the same dosage of statin therapy throughout the 12 weeks of ER metoprolol treatment. None of the other participants received lipidlowering therapy before or during the trial period. As expected, a large portion of this sample of type 2 diabetics were insulin-resistant. Using the National Cholesterol Education Panel criteria for defining the metabolic syndrome, of the 28 participants, or 93% of this sample, had the metabolic syndrome. The 2 patients who did not meet criteria for the metabolic syndrome both had a BMI <30 kg/m 2, a high-density lipoprotein cholesterol level above threshold, and a triglyceride level below threshold for metabolic syndrome criteria. Figure. The insulin sensitivity index (M/I), measured by the euglycemic hyperinsulinemic clamp procedure is plotted on the y-axis. For each participant, M/I is depicted before extended-release metoprolol succinate (ER metoprolol) treatment (Pre) and during ER metoprolol treatment with a line connecting the pre- and post M/I value. M/I values <7.5 mg/kg*min 100 reflect relative insulin resistance. Discussion Data from this study suggest that the b1-selective adrenergic receptor blocking agent ER metoprolol has no effect on insulin sensitivity in type 2 diabetic patients with hypertension, at least over the 4-month period of the study. In this study, the insulin sensitivity measures, derived by the euglycemic hyperinsulinemic clamp procedure, were unchanged following 12 weeks of ER metoprolol therapy. There was no change in HbA 1c values and there was no change in other indirect estimates of insulin sensitivity, including those assessed by the HOMA and QUICKI. Plasma lipid levels were not significantly changed in these diabetic patients. Given that the study was adequately powered to detect a clinically relevant change from baseline in insulin sensitivity using the most rigorous methodology, the absence of a statistically significant change in M/I provides good evidence that the addition of this selective b-blocker to an antihypertensive regimen does not result in negative metabolic consequences. In previous reports, the effects of antihypertensive medications, including b-blockers, on insulin VOL. 10 NO. 1 January 2008 THE Journal of Clinical Hypertension 55 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.

6 sensitivity have been examined. The effects of other b-blockers that have been reported on insulin sensitivity range from a substantial reduction in insulin sensitivity by the nonselective b-blocker propranolol to an increase in insulin sensitivity with other b-blockers with vasodilating properties such as carvedilol and celiprolol. 6,22 Deterioration in insulin sensitivity (or development of insulin resistance) may mediate an unfavorable trend in plasma lipids and glucose metabolism. A shift toward a more atherogenic lipid profile during treatment with b-blocking drugs has also been described. 23 Patients treated with nonselective b-blockers, which block both b1 and b2 receptors, may have a slight increase in total peripheral resistance. Because stimulation of the b2 receptors causes vasodilation, the nonselective b-blockers, which also block the b2 receptors, might then also prevent the b2-stimulated increase in blood flow. If the change in peripheral resistance translates to a reduction in peripheral blood flow, there could be a resultant adverse effect on insulin sensitivity due to restriction in nutrient delivery to tissue cells. Theoretically, selective b-blockers, which block only the b1 receptors, would have less effect on insulin sensitivity. 24 Although metoprolol tartrate is a selective b adrenergic blocker, this short-acting agent has been reported to decrease insulin sensitivity. 25 Insulin sensitivity was compared between nondiabetic hypertensive patients treated with carvedilol, a nonselective b-blocker with a1-blocking properties, and patients treated with metoprolol tartrate. Insulin sensitivity was quantified by insulin clamp before and following 12 months treatment with each b-blocking drug. The investigators reported a 14% reduction in insulin sensitivity following metoprolol tartrate therapy and a slight increase in insulin sensitivity following carvedilol therapy. 19 A recent large randomized clinical trial examined the metabolic effects of carvedilol compared with metoprolol tartrate in patients with type 2 diabetes and hypertension. 9 An increase in HbA 1c was reported following metoprolol but not carvedilol. The HOMA equation, used to estimate insulin sensitivity, was lower (indicating an increase in insulin sensitivity) with carvedilol therapy and no change in HOMA with metoprolol tartrate therapy. 9 The previous reports appear to indicate that the selective b adrenergic blocker metoprolol tartrate (as other b-blockers) may have an adverse metabolic effect that is mediated through a reduction in insulin sensitivity. The data in our study on metoprolol succinate are not consistent with these previous reports, however. In this study, which used the extended-release preparation, there was no effect of this medication on insulin sensitivity as quantified by the insulin clamp procedure. The neutral effect of metoprolol succinate on insulin sensitivity may be due to pharmacokinetic differences between extended-release and the shorter-acting preparations. The pharmacokinetics and pharmacodynamics of metoprolol succinate have been compared with metoprolol tartrate and to atenolol in a double-blind crossover study by Darmansjah and associates 26 Differences in pharmacokinetics between the 2 metoprolol preparations have been identified. The t max of the extended-release formulation was significantly delayed compared with the short-acting compound. The peak-trough plasma level fluctuation index of metoprolol succinate was also significantly smaller than that of metoprolol tartrate, and the mean relative bioavailability of the succinate was lower. The plasma concentration profile of the extended-release preparation was relatively even without marked peaks and troughs over the dose interval that was observed with the short-acting metoprolol. The pharmacokinetic differences between the 2 preparations demonstrated in that study suggest that the adverse effect on insulin sensitivity reported with the shorter-acting agent may be due to relatively higher plasma levels of the drug and greater fluctuation in plasma concentration. This pharmacokinetic pattern could overcome, to some degree, the b selectivity of metoprolol tartrate, whereas the relatively lower plasma levels observed with metoprolol succinate preserve the b selectivity. A substantial portion of the participants in this study were overweight, which is typical of adults with type 2 diabetes. A change in body weight may also have an effect on insulin sensitivity. Participants were not placed on rigorous diets but were instructed to maintain their usual diet patterns. While there was some slight weight change among some of the patients in this study, there was no consistent trend of weight gain or weight loss, and the mean weight and mean BMI of the study sample was unchanged over the 3 months of the trial. Analysis of the data on body weight detected no effect of weight change on insulin sensitivity change during treatment with ER metoprolol; however, the observation period of 12 weeks for this study was relatively short. It is possible that a longer exposure or excessive weight gain over an extended period could have a late effect on insulin sensitivity. It is also plausible that the RAAS inhibitor therapy that all diabetic patients were receiving 56 THE Journal of Clinical Hypertension VOL. 10 NO. 1 January 2008 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.

7 in this study provided some additional benefit in countering adverse effects on insulin sensitivity. Conclusions Antihypertensive therapy with a long-acting, selective b-blocking agent ER metoprolol had no effect on insulin sensitivity in diabetic patients with hypertension who were also being treated with an RAAS inhibitor plus a diuretic. There were no changes in insulin clamp measures of insulin sensitivity, indirect estimates of insulin sensitivity (HOMA or QUICKI), or HbA 1c. These results demonstrate that when treatment with a b-blocker is indicated in a diabetic patient, this agent can be used without unfavorable effects on insulin metabolism. Acknowledgment: This work was supported by an investigatorinitiated research grant from AstraZeneca Pharmaceuticals, the manufacturer of extended-release metoprolol succinate. References 1 Stamler J, Vaccaro O, Neaton JD, et al. 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Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285: Sica DA. b-blockers in hypertension: a reassessment of the benefit of combined a-/b-blockade. J Clin Hypertens (Greenwich). 2007;9(4 suppl 3): Grimm RH. Antihypertensive therapy: taking lipids into consideration. Am Heart J. 1991;122: Lithell H, Pollare T, Vessby B. Metabolic effects of pindolol and propranolol in a double-blind cross-over study n hypertensive patients. Blood Press. 1992;1: Pollare T, Lithell HO, Selinus I, et al. Sensitivity to insulin during treatment with atenolol and metroprolol: a randomized, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ. 1989;298: Darmansjah I, Wong E, Setiawati A, et al. Pharmacokinetic and pharmacodynamic properties of controlled release (CR/ZOK) metoprolol in healthy Oriental subjects: A comparison with conventional formulations of metoprolol and atenolol. J Clin Pharmacol. 1990;30:S39 S45. Fast, Easy, Accessible. Enrich your learning experience. Log onto CME credit available from Winthrop- University Hospital. This activity has been approved for a maximum of 1 Category 1 credit and expires 6 months after publication. Instant CME Credit VOL. 10 NO. 1 January 2008 THE Journal of Clinical Hypertension 57 The Journal of Clinical Hypertension (ISSN ) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT Copyright 2007 by Le Jacq. All rights reserved.