Review Paper • C M E

Do the Metabolic Effects of β Blockers

Make Them Leading or Supporting
Antihypertensive Agents in the Treatment
of Hypertension?
Panteleimon A. Sarafidis, MD;1 George L. Bakris, MD2

Reduction of blood pressure to guideline goals better metabolic profile when compared with those
(i.e., <130/80 mm Hg) in persons with diabe- that purely affect β receptors. Thus, vasodilat-
tes is crucial to optimally reduce cardiovascular ing β blockers, by being neutral on glycemic and
events and kidney disease progression. Since many metabolic factors, are associated with less use of
patients will be >20/10 mm Hg above this goal, additional medication for lipid or glucose control
most guidelines recommend using agents that and may provide a potentially greater cardiovascu-
block the renin–angiotensin system in concert with lar risk reduction by virtue of these effects. (J Clin
a thiazide-like diuretic to achieve goal blood pres- Hypertens. 2006;8:351–356) ©2006 Le Jacq Ltd.
sure. Meta-analyses of clinical trials indicate that
while all classes of antihypertensive agents reduce
cardiovascular risk, they exert different effects
on glucose utilization and lipids and, hence, may
affect morbidity. Specifically, β blockers, in general,
H ypertension and type 2 diabetes mellitus are
major cardiovascular risk factors that com-
monly cluster in the same individual in the context
worsen insulin resistance and increase triglycerides of the metabolic syndrome. Achieving the recom-
in a dose-dependent fashion. Moreover, they are mended blood pressure guideline goal of <130/80
not recommended as initial therapy for hyperten- mm Hg in those with diabetes is possible with the
sion treatment in the absence of heart failure or use of any major antihypertensive class.1 In general,
recent myocardial infarction, especially in the however, combinations of antihypertensive agents
elderly. Recent studies support the notion that are needed if blood pressure is >20/10 mm Hg
newer β blockers with vasodilating effects have a above this goal. Most guidelines recommend block-
ers of the renin-angiotensin-aldosterone system in
From the 1st Department of Medicine, AHEPA concert with thiazide-like diuretics as initial therapy
Hospital, Aristotle University of Thessaloniki, Greece;1 for most people who require two-drug therapy.2,3
and the Department of Preventive Medicine, Rush Results of a recent meta-analysis of clinical tri-
University Hypertension Center, Chicago, IL2 als performed over the past decade indicate that
Address for correspondence: while different classes of antihypertensive agents
George L. Bakris, MD, Department of Preventive
Medicine, Rush University Medical Center, 1700 West all reduce cardiovascular risk, they exert differ-
Van Buren, Suite 470, Chicago, IL 60612 ent effects on glucose utilization and, hence, may
E-mail: gbakris@earthlink.net affect morbidity. Specifically, drugs that block
Manuscript received October 3, 2005; the renin-angiotensin-aldosterone system, such as
revised November 23, 2005; angiotensin-converting enzyme (ACE) inhibitors
accepted December 6, 2005
or angiotensin receptor blockers and calcium
www.lejacq.com ID: 4679 channel blockers have neutral or beneficial effects

VOL. 8 NO. 5 MAY 2006 THE JOURNAL OF CLINICAL HYPERTENSION 351

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 on carbohydrate and lipid metabolism, whereas insulin sensitivity, and development of new-onset
thiazide diuretics and β blockers worsen insulin diabetes. We discuss the comparative effects of
resistance in a dose-dependent fashion.4–6 In spite both traditional and vasodilating β blockers on
of this adverse effect on glycemic and metabolic carbohydrate metabolism in the context of clinical
control, clinical trials of 3- to 5-years’ duration management culminating with suggestions for use
that used a β blocker demonstrate a reduction in in practice.
cardiovascular events, especially in patients with
diabetes following a myocardial infarction or INSULIN SENSITIVITY AND RISK OF
heart failure.7–10 The United Kingdom Prospective NEW-ONSET DIABETES
Diabetes Study (UKPDS)11 clearly demonstrates the In clinical studies that have used the euglycemic
cardiovascular benefits of a β blocker compared hyperinsulinemic clamp technique (the most reliable
with an ACE inhibitor in patients with hyperten- available method to estimate insulin sensitivity),
sion and type 2 diabetes. In this trial, as well, the treatment with conventional β blockers, either non-
metabolic profile did not favor the β blocker, yet selective like propranolol4 or β1-selective like ateno-
there was no difference in the cardiovascular out- lol18,19 or metoprolol,13,18 significantly decrease insu-
comes after a follow-up period of 8 years. This is lin sensitivity in hypertensive patients. This decrease
why there is a compelling indication for their use in in insulin sensitivity by these β blockers would be
those with diabetes.2,3,11,12 Moreover, all the older expected to worsen glycemic control in patients with
trials required two or more drugs to reduce blood diabetes and impaired glucose tolerance. Conversely,
pressure to <140/90 mm Hg, and thiazide diuret- in those without diabetes, a decrease in insulin sensi-
ics were used as a second agent in all such trials. tivity would not result in elevation of blood glucose
It should be noted that in these trials, there was a levels as long as the pancreatic β cells secrete the
worsening of glucose and lipid profiles when they necessary amount of insulin.
were measured; however, a benefit on cardiovascu- One hypothesis is that a higher insulin demand
lar outcome was still noted. accompanies the process of aging and increases in
Recent studies support the notion that newer body weight. When the pancreatic β cells can no
β blockers with vasodilating effects have a bet- longer compensate for the increasing insulin resis-
ter metabolic profile when compared with those tance, impaired glucose tolerance and ultimately
that purely affect β receptors. Thus, vasodilating diabetes appear.20 This hypothesis is supported
β blockers, such as carvedilol, by being neutral on by studies that examine the incidence of new-
glycemic and metabolic factors, may result in lower onset diabetes in the presence of β blockers. The
morbidity with a lower incidence of new-onset dia- Atherosclerosis Risk in Communities (ARIC)21
betes. Such agents are associated with less use of cohort study demonstrated that after more than
additional medication for lipid or glucose control a 6-year follow-up of 3804 hypertensive subjects
and may provide a potentially greater cardiovas- treated with antihypertensive therapy, those who
cular risk reduction by virtue of these effects.13–16 received β blockers had a 28% higher risk of type 2
However, there is only one prospective comparator diabetes compared with those taking no medication
trial of different β blockers, and this trial had no or other antihypertensive agents, including thiazide
cardiovascular end points.16 Thus, the potential diuretics. Many other prospective trials have new
additional benefit of the vasodilating β blockers on diabetes outcomes similar to those in the ARIC
cardiovascular outcome, in spite of their favorable study and are summarized in the Table.5 Note,
metabolic effects, remains to be proven. however, that while all these trials show worsening
The cardiovascular benefit of many β blockers, or development of new-onset diabetes in the short
i.e., propranolol, atenolol, metoprolol, and others, term, they all also show mortality reduction com-
is associated with detrimental effects on insulin parable to the comparator therapy.
sensitivity, glycemic control, and incidence of A number of methodologic issues limit the con-
type 2 diabetes.5,15,17 Clinical evidence, however, clusions extrapolated from these studies. The limi-
supports the notion that β blockers with vasodilat- tations include the fact that: 1) none of the studies
ing effects are associated with far fewer adverse published to date examine diabetes incidence as a
metabolic effects and, hence, are a valuable tool primary end point12,21–24; 2) more than half the par-
for hypertension treatment in patients with the ticipants in all the trials received a second agent that
metabolic syndrome.15,16 This review summarizes could also influence glycemic control.23–25 (In some
the clinical evidence on β blockers and their effects of these studies, an ACE inhibitor23,26 or a calcium
on carbohydrate metabolism, i.e., glucose control, channel blocker27 was compared with diuretics

352 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 5 MAY 2006

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 or β blockers in various combinations; thus, a net Table. Summary of Post-Hoc Analyses of Outcome Studies
effect of the latter cannot be easily assessed); and 3) Illustrating New-Onset Diabetes (NOD)
detection bias could have occurred in these studies, STUDY TREATMENT 1 Δ IN NOD TREATMENT 2
in that some of the studies were open-label with HOPE Placebo ± BB/ 52% vs. ACEI ± BB/
blinded end point evaluation.11,23 Thus, the search diuretic diuretic
for a diagnosis of diabetes may have been more ALLHAT Diuretic 43% vs. ACEI
intensive in those who received β blockers, based on INSIGHT Diuretic ± BB 43% vs. DHP-CCB
an increased incidence from previous studies. ASCOT Diuretic ± BB 32% vs. DHP-CCB–
based
EFFECTS OF β BLOCKERS: INSULIN LIFE BB + diuretic 32% vs. ARB
SENSITIVITY AND GLYCEMIC CONTROL VALUE DHP-CCB– 25% vs. ARB-based
There are several mechanisms described that are based
possibly responsible for the metabolic effects of ALLHAT Diuretic 18% vs. DHP-CCB
β blockers. In healthy persons, insulin yields INVEST BB-based + 17% vs. NDHP-
vasodilation and increases blood flow to the skel- diuretic CCB–based
etal muscles, an action tightly coupled with an CHARM Placebo ± BB/ 17% vs. ARB ± BB/
increase of glucose disposal in the same tissue.28 diuretic diuretic
In contrast, in persons with insulin resistance, CAPPP Diuretics, BB 13% vs. ACEI
endothelium-dependent insulin-mediated vasodi- AASK BB + diuretic 28% vs. ACEI
lation is impaired; this impairment is considered Δ=change; HOPE=Heart Outcomes Prevention Evaluation
an important cause of reduced insulin-stimulated study; BB=β blocker; ACEI=angiotensin-convert-
glucose uptake in the periphery.28,29 Conversely, ing enzyme inhibitor; ALLHAT=Antihypertensive and
acute sympathetic nervous system stimulation in Lipid-Lowering Treatment to Prevent Heart Attack
Trial; INSIGHT=International Nifedipine GITS Study:
healthy individuals lowers insulin-stimulated glu-
Intervention as a Goal in Hypertension Treatment;
cose uptake in muscles through vasoconstriction DHP=dihydropyridine; CCB=calcium channel blocker;
and blood flow reduction.30,31 This effect is medi- ASCOT=Anglo-Scandinavian Cardiac Outcomes Trial;
ated by α1-adrenergic pathways, as evidenced LIFE=Losartan Intervention For Endpoint Reduction in
in studies with direct α- and β-blockade,32 and Hypertension study; ARB=angiotensin receptor blocker;
further supported by the vasodilating and insulin- VALUE=Valsartan Antihypertensive Long-Term Use
sensitizing effects of α-adrenergic blockers.33 Thus, Evaluation; INVEST=International Verpamil-Trandolopril
treatment with conventional β blockers, an unop- Study; NDHP=non-DHP; CHARM=Candesartan in Heart
posed α1 activity, would cause vasoconstriction Failure: Assessment of Reduction in Mortality and Morbidity
trial; CAPPP=Captopril Prevention Project; AASK=African
and decreased blood flow to muscles.34,35
American Study of Kidney Disease and Hypertension.
Treatment with β blockers also affects insulin Modified from J Am Coll Cardiol. 2004;44:509–512.5
secretion from pancreatic β cells. In particular,
nonselective β blockers have been found to decrease
the first phase of insulin secretion, possibly due to hepatic glycogenolysis, which leads to elevated
impairment of β2-mediated insulin release.18,34,36 hepatic glucose production after meals and, conse-
The attenuation of first-phase insulin secretion quently, contributes to loss of glycemic control.37,38
represents a crucial step in the natural history of Sympathetic activation stimulates glyconeogenesis
type 2 diabetes and has been suggested to be an and glycogenolysis and inhibits glycogen synthesis
important predictor of the disease.37 Hence, this in the liver. Although the relative importance of
action of β blockers could be a very important con- α- and β-adrenergic receptors in mediating cat-
tributor to the development of type 2 diabetes. echolamine-induced hepatic glucose production in
Weight gain has been proposed as another contrib- humans in vivo is unclear, in rats, α2 receptors are
utor to decreased insulin sensitivity associated with involved.39 Thus, if α receptors play a major role
β blockers, as these agents increase body weight.11,16 in humans, unopposed α activity in the presence of
However, weight gain does not appear to be a major β-blockade could result in enhanced hepatic glucose
contributor to worsening of insulin resistance, as it output, increasing the risk for type 2 diabetes.
failed to independently predict worsening of glycemic
control in a number of studies, including a large long- VASODILATING β BLOCKERS, INSULIN
term study of more than 15,000 people.18,21 SENSITIVITY, AND GLYCEMIC CONTROL
Another mechanism that contributes to insu- Studies of β blockers with vasodilating effects,
lin-resistance is the inability of insulin to suppress such as carvedilol and celiprolol, have neutral or

VOL. 8 NO. 5 MAY 2006 THE JOURNAL OF CLINICAL HYPERTENSION 353

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 beneficial effects on glycemic control and insulin favorable metabolic effects on lipids and glucose
sensitivity. Several years ago, dilevalol, a β1-selec- control in patients with hypertension.42 Thirty
tive blocker with β2-agonistic action, was found hypertensive hyperlipidemic men and women were
to improve insulin sensitivity by about 10% in randomized to receive either atenolol (50 mg
hypertensive patients;17 however, this compound daily) or nebivolol (5 mg daily). Atenolol sig-
was withdrawn from the market due to side effects. nificantly increased triglyceride levels by 19%,
Celiprolol, a similar compound with better toler- which was not seen with nebivolol. Atenolol also
ability that is marketed in Europe, is also associ- increased lipoprotein(a) by 30%. Both agents,
ated with a 35% improvement in insulin sensitivity however, decreased serum high-sensitivity C-reac-
following a year of treatment.14 tive protein levels, whereas only nebivolol reduced
Carvedilol, a nonselective β blocker with insulin resistance. Similar effects on glycemic con-
α1-blocking and antioxidant effects, also improves trol using a euglycemic clamp were also observed
insulin sensitivity.13 In two separate studies that in a separate study with nebivolol.43
compared carvedilol with either metoprolol or
atenolol, an improvement in insulin sensitivity CONCLUSION
was observed after a 3- and 6-month time period, Antihypertensive treatment with traditional β blockers
respectively.13,15 The results of these small studies reduces cardiovascular risk in persons with diabetes;
were corroborated by the results of the Glycemic however, these agents are underutilized in patients
Effects in Diabetes Mellitus: Carvedilol-Metoprolol with diabetes and/or the metabolic syndrome, possibly
Comparison in Hypertensives (GEMINI) trial,16 a due to their detrimental effects on insulin sensitivity
multicenter trial of 1235 subjects with hyperten- and the incidence of type 2 diabetes.9,12,44,45
sion and type 2 diabetes. In this trial, patients Should these agents be used as initial therapy
were already receiving an ACE inhibitor or an for the treatment of hypertension? In general,
angiotensin receptor blocker and were random- most guidelines argue against initial therapy unless
ized to carvedilol or metoprolol twice daily. After compelling indications are present, such as heart
5 months of maintenance therapy, glycosylated failure, high sympathetic tone, or immediately fol-
hemoglobin increased in the metoprolol but not lowing a myocardial infarction. More precisely,
in the carvedilol group. When insulin resistance although these agents reduce blood pressure and,
was assessed by the homeostasis model, the insulin hence, cardiovascular events, there are other agents
resistance index was significantly decreased with available with better tolerability and similar effi-
carvedilol but not metoprolol. These differences in cacy in reducing cardiovascular events; therefore,
glycemic control could not be explained by differ- an agent that is better tolerated should be used. In
ences in blood pressure, weight gain, or other fac- patients with the metabolic syndrome who have
tors. These findings support both a neutral effect impaired fasting glucose levels >100 but <126
on glycemic control and improved insulin sensitiv- mg/dL, a β blocker with neutral glycemic effects,
ity with the use of vasodilating β blockers when if needed for initial therapy, would be preferred to
compared with agents that only block β receptors. reduce the risk of worsening glycemic control and
The neutral effects of newer β-blocking agents hastening the development of diabetes. In persons
on glycemic control and insulin sensitivity with established diabetes already receiving oral
could be explained in part by their α-blocking hypoglycemic medications, β blockers, in general,
or β2-stimulating capacity, resulting in vasodila- are excellent third- and fourth-line agents when
tion and, hence, improved blood flow to the skel- needed for blood pressure control and should be
etal muscle.40 Therefore, the beneficial effects of used. Studies comparing newer vasodilating to
carvedilol on glycemic parameters could also be conventional β-blocking agents show a neutral
explained by its hemodynamic effects, at least in effect on glycemic control and improved insulin
part. It must be noted that carvedilol has an α- to sensitivity with vasodilating β blockers. This sug-
β-blockade ratio different from labetalol and has gests that these agents could be used in subjects
fewer side effects associated with vasodilation, with hypertension with or without diabetes with-
such as postural hypotension and dizziness.41 out fear of deterioration of these parameters. The
This difference in tolerability is of particular definite answer on the possible benefits of vasodi-
importance in patients with diabetic neuropathy lating over conventional β blockers will come from
and postural hypotension. a randomized trial of outcomes in patients with
Nebivolol, a β1-selective blocker that modu- hypertension and diabetes similar to those already
lates nitric oxide release, has also demonstrated available in patients with heart failure.46

354 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 5 MAY 2006

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 REFERENCES pathologic mechanisms and treatment: current status and
therapeutic possibilities. Prog Drug Res. 1998;51:33–94.
1 Turnbull F, Neal B, Algert C, et al. Effects of different blood 21 Gress TW, Nieto FJ, Shahar E, et al. Hypertension and
pressure-lowering regimens on major cardiovascular events antihypertensive therapy as risk factors for type 2 diabe-
in individuals with and without diabetes mellitus: results tes mellitus. Atherosclerosis Risk in Communities Study.
of prospectively designed overviews of randomized trials. N Engl J Med. 2000;342:905–912.
Arch Intern Med. 2005;165:1410–1419. 22 Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular
2 Seventh report of the Joint National Committee on morbidity and mortality in the Losartan Intervention For
Prevention, Detection, Evaluation, and Treatment of High Endpoint Reduction in Hypertension study (LIFE): a ran-
Blood Pressure. Hypertension. 2003;42:1206–1252. domised trial against atenolol. Lancet. 2002;359:995–1003.
3 2003 European Society of Hypertension-European Society 23 Hansson L, Lindholm LH, Ekbom T, et al. Randomised
of Cardiology guidelines for the management of arterial trial of old and new antihypertensive drugs in elder-
hypertension. J Hypertens. 2003;21:1011–1053. ly patients: cardiovascular mortality and morbidity the
4 Lithell HO. Effect of antihypertensive drugs on insulin, glucose, Swedish Trial in Old Patients with Hypertension-2 study.
and lipid metabolism. Diabetes Care. 1991;14:203–209. Lancet. 1999;354:1751–1756.
5 Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies 24 Major outcomes in high-risk hypertensive patients ran-
and risk for development of diabetes. J Am Coll Cardiol. domized to angiotensin-converting enzyme inhibitor or
2004;44:509–512. calcium channel blocker vs diuretic: the Antihypertensive
6 Sowers JR, Bakris GL. Antihypertensive therapy and and Lipid-Lowering Treatment to Prevent Heart Attack
the risk of type 2 diabetes mellitus. N Engl J Med. Trial (ALLHAT). JAMA. 2002;288:2981–2997.
2000;342:969–970. 25 Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A
7 Packer M. Do beta-blockers prolong survival in heart failure calcium antagonist vs a non-calcium antagonist hypertension
only by inhibiting the beta1-receptor? A perspective on the treatment strategy for patients with coronary artery disease.
results of the COMET trial. J Card Fail. 2003;9:429–443. the International Verapamil-Trandolapril Study (INVEST): a
8 Tandon P, McAlister FA, Tsuyuki RT, et al. The use of beta- randomized controlled trial. JAMA. 2003;290:2805–2816.
blockers in a tertiary care heart failure clinic: dosing, toler- 26 Hansson L, Lindholm LH, Niskanen L, et al. Effect of
ance, and outcomes. Arch Intern Med. 2004;164:769–774. angiotensin-converting-enzyme inhibition compared with
9 Haas SJ, Vos T, Gilbert RE, et al. Are beta-blockers as conventional therapy on cardiovascular morbidity and
efficacious in patients with diabetes mellitus as in patients mortality in hypertension: the Captopril Prevention Project
without diabetes mellitus who have chronic heart failure? (CAPPP) randomised trial. Lancet. 1999;353:611–616.
A meta-analysis of large-scale clinical trials. Am Heart J. 27 Hansson L, Hedner T, Lund-Johansen P, et al. Randomised
2003;146:848–853. trial of effects of calcium antagonists compared with diuret-
10 Packer M, Fowler MB, Roecker EB, et al. Effect of carve- ics and beta-blockers on cardiovascular morbidity and
dilol on the morbidity of patients with severe chronic heart mortality in hypertension: the Nordic Diltiazem (NORDIL)
failure: results of the carvedilol prospective randomized study. Lancet. 2000;356:359–365.
cumulative survival (COPERNICUS) study. Circulation. 28 Steinberg HO, Baron AD. Vascular function, insulin resis-
2002;106:2194–2199. tance and fatty acids. Diabetologia. 2002;45:623–634.
11 Efficacy of atenolol and captopril in reducing risk of mac- 29 Sartori C, Scherrer U. Insulin, nitric oxide and the sympathetic
rovascular and microvascular complications in type 2 dia- nervous system: at the crossroads of metabolic and cardiovas-
betes: UKPDS 39. UK Prospective Diabetes Study Group. cular regulation. J Hypertens. 1999;17:1517–1525.
BMJ. 1998;317:713–720. 30 Lembo G, Capaldo B, Rendina V, et al. Acute noradrener-
12 Bakris GL, Gaxiola E, Messerli FH, et al. Clinical out- gic activation induces insulin resistance in human skeletal
comes in the diabetes cohort of the International Verapamil muscle. Am J Physiol. 1994;266(2 pt 1):E242–E247.
SR-Trandolapril study. Hypertension. 2004;44:637–642. 31 Tappy L, Girardet K, Schwaller N, et al. Metabolic effects
13 Jacob S, Rett K, Wicklmayr M, et al. Differential effect of of an increase of sympathetic activity in healthy humans.
chronic treatment with two beta-blocking agents on insulin Int J Obes Relat Metab Disord. 1995;19:419–422.
sensitivity: the carvedilol-metoprolol study. J Hypertens. 32 Scherrer U, Sartori C. Insulin as a vascular and sympatho-
1996;14:489–494. excitatory hormone: implications for blood pressure regu-
14 Malminiemi K. Association between serum lipids, glucose lation, insulin sensitivity, and cardiovascular morbidity.
tolerance, and insulin sensitivity during 12 months of celip- Circulation. 1997;96:4104–4113.
rolol treatment. Cardiovasc Drugs Ther. 1995;9:295–304. 33 Pollare T, Lithell H, Selinus I, et al. Application of prazosin
15 Giugliano D, Acampora R, Marfella R, et al. Metabolic is associated with an increase of insulin sensitivity in obese
and cardiovascular effects of carvedilol and atenolol in patients with hypertension. Diabetologia. 1988;31:415–420.
non-insulin-dependent diabetes mellitus and hyperten- 34 Lithell H, Pollare T, Vessby B. Metabolic effects of pindo-
sion. A randomized, controlled trial. Ann Intern Med. lol and propranolol in a double-blind cross-over study in
1997;126:955–959. hypertensive patients. Blood Press. 1992;1:92–101.
16 Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects 35 Lund-Johansen P, Omvik P, Nordrehaug JE. Long-term
of carvedilol vs metoprolol in patients with type 2 diabetes hemodynamic effects of antihypertensive treatment. Clin
mellitus and hypertension: a randomized controlled trial. Investig. 1992;70(suppl 1):S58–S64.
JAMA. 2004;292:2227–2236. 36 Kaneto A, Miki E, Kosaka K. Effect of beta and beta2 adreno-
17 Haenni A, Lithell H. Treatment with a beta-blocker with receptor stimulants infused intrapancreatically on glucagon
beta 2-agonism improves glucose and lipid metabolism in and insulin secretion. Endocrinology. 1975;97:1166–1173.
essential hypertension. Metabolism. 1994;43:455–461. 37 DeFronzo RA, Ferrannini E. Insulin resistance. A multi-
18 Pollare T, Lithell H, Selinus I, et al. Sensitivity to insulin faceted syndrome responsible for NIDDM, obesity, hyper-
during treatment with atenolol and metoprolol: a ran- tension, dyslipidemia, and atherosclerotic cardiovascular
domised, double blind study of effects on carbohydrate disease. Diabetes Care. 1991;14:173–194.
and lipoprotein metabolism in hypertensive patients. BMJ. 38 Groop LC, Bonadonna RC, DelPrato S, et al. Glucose and
1989;298:1152–1157. free fatty acid metabolism in non-insulin-dependent diabe-
19 Pollare T, Lithell H, Morlin C, et al. Metabolic effects of dil- tes mellitus. Evidence for multiple sites of insulin resistance.
tiazem and atenolol: results from a randomized, double-blind J Clin Invest. 1989;84:205–213.
study with parallel groups. J Hypertens. 1989;7:551–559. 39 Nonogaki K, Iguchi A. Role of central neural mechanisms
20 Turner NC, Clapham JC. Insulin resistance, impaired in the regulation of hepatic glucose metabolism. Life Sci.
glucose tolerance and non-insulin-dependent diabetes, 1997;60:797–807.

VOL. 8 NO. 5 MAY 2006 THE JOURNAL OF CLINICAL HYPERTENSION 355

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 40 Reaven GM. Role of insulin resistance in human disease hypertensive patients. J Hypertens. 2001;19:1429–1435.
(syndrome X): an expanded definition. Annu Rev Med. 44 Abbott KC, Trespalacios FC, Agodoa LY, et al. Beta-
1993;44:121–131. blocker use in long-term dialysis patients: association with
41 Tomlinson B, Bompart F, Graham BR, et al. Vasodilating hospitalized heart failure and mortality. Arch Intern Med.
mechanism and response to physiological pressor stimuli 2004;164:2465–2471.
of acute doses of carvedilol compared with labetalol, pro- 45 Psaty BM, Lumley T, Furberg CD, et al. Health out-
pranolol and hydralazine. Drugs. 1988;36(suppl 6):37–47. comes associated with various antihypertensive therapies
42 Rizos E, Bairaktari E, Kostoula A, et al. The combination used as first-line agents: a network meta-analysis. JAMA.
of nebivolol plus pravastatin is associated with a more ben- 2003;289:2534–2544.
eficial metabolic profile compared to that of atenolol plus 46 Poole-Wilson PA, Swedberg K, Cleland JG, et al.
pravastatin in hypertensive patients with dyslipidemia: a Comparison of carvedilol and metoprolol on clinical
pilot study. J Cardiovasc Pharmacol Ther. 2003;8:127–134. outcomes in patients with chronic heart failure in the
43 Poirier L, Cleroux J, Nadeau A, et al. Effects of nebivolol Carvedilol or Metoprolol European Trial (COMET): ran-
and atenolol on insulin sensitivity and haemodynamics in domised controlled trial. Lancet. 2003;362:7–13.

356 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 5 MAY 2006

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 CME Questions
Todd C. Kerwin, MD, Section Editor
Winthrop Cardiology Associates, Mineola, NY

INSTRUCTIONS FOR COMPLETING THIS FORM: Read the selected paper and answer all the questions that follow. After each
question there is a series of possible correct answers. Please select the one best answer for each and place your selection on the answer
grid. YOU MUST ALSO COMPLETE THE CME EVALUATION SECTION and return the form within 6 months of the paper’s
publication to receive credit. Letters of credit will be mailed to participants biannually.
ACCREDITATION STATEMENT: Winthrop-University Hospital (WUH) is accredited by the Accreditation Council for Continuing Medical
Education (ACCME) to sponsor continuing medical education for physicians. WUH designates this Continuing Medical Education activity for a
maximum of (1) credit hour in Category 1 credit towards the AMA Physicians’ Recognition Award. Each physician should claim only those hours
of credit that he/she actually spent on the educational activity. WUH relies upon faculty participants in its CME programs to provide educational
information that is objective and as free of bias as possible. In this spirit, and in accordance with the guidelines of the program sponsor, faculty
participants are expected to indicate any commercial relationship that might be perceived as a real or apparent conflict of interest.
EDITOR DISCLOSURES: Dr. Kerwin is on the Speaker’s Bureau for Aventis and Takeda Pharmaceuticals.
AUTHOR DISCLOSURES: Panteleimon A. Sarafidis, MD: no relationships to disclose. George L. Bakris, MD: AstraZeneca
Pharmaceuticals LP, GlaxoSmithKline, Forest Laboratories, Inc., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Abbott
Laboratories, Sankyo Pharma Inc.—consultant, grant recipient.
OBJECTIVE AND TARGET AUDIENCE: All clinicians are eligible to receive credit. At the conclusion of this activity, participants
should be able to: 1) summarize the important points discussed in the paper reviewed; 2) identify patients to whom the paper is rel-
evant; 3) modify management practices as new information is learned; and 4) identify deficiencies in their knowledge base.

Please Select the One Best Answer for Each and Place Your Selection on the Answer Grid.

1. Which of the following agents have been asso- 3. Which of the following is not a proposed
ciated with a worsening of insulin resistance? mechanism for the metabolic effects of
A __ Beta blockers and calcium channel blockers β blockers?
B __ Beta blockers and thiazide diuretics A __ Unopposed α activity resulting in a
C __ Alpha blockers and thiazide diuretics decrease in blood flow to muscle tissue
D __ Alpha and β blockers B __ Attenuation of first-phase insulin secretion
by pancreatic β cells
2. Studies such as the Atherosclerosis Risk in C __ Unopposed α activity resulting in reduc-
Communities (ARIC) trial demonstrated which tion of hepatic glucose output
of the following effects in patients treated with D __ Weight gain
β blockers?
A __ No apparent metabolic effect 4. Which of the following drugs is considered a
B __ Evidence of improved insulin sensitivity vasodilating β blocker?
C__ An increase in the incidence of type 2 diabetes A __ Carvedilol
D __ A higher mortality rate than in patients B __ Atenolol
treated with other agents C __ Metoprolol
D __ Pindolol
5. Which of the following statements regarding the
vasodilating β blockers is not true?
A __ They have neutral to beneficial effects on
glycemic control.
B __ They have neutral to beneficial effects on
insulin resistance.
C __ Carvedilol may be better tolerated than
other α-blocking agents.
D __ They are less effective than nonvasodilat-
ing β blockers in lowering blood pressure.

CME Answers are available from The Journal of Clinical Hypertension page at www.lejacq.com

VOL. 8 NO. 5 MAY 2006 THE JOURNAL OF CLINICAL HYPERTENSION 357

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.
 CME Answer Grid
Answer the questions from the previous page by selecting the best choice of A, B, C, or D
Questions: 1.__ 2.__ 3.__ 4.__ 5.__

CME Evaluation
Agree Disagree
1. My knowledge was enhanced by this activity. 1.__ 2.__ 3.__ 4.__ 5.__

2. The activity helped to clarify issues

specific to hypertensive patients. 1.__ 2.__ 3.__ 4.__ 5.__

3. The information obtained from this exercise

will have an impact on my care of patients. 1.__ 2.__ 3.__ 4.__ 5.__

4. The format of the exercise was useful. 1.__ 2.__ 3.__ 4.__ 5.__

5. Suggestions for future topics:

Where to Send the Completed CME Form

Please print all information.
Please submit a $5 administrative fee in the form of a check
made out to the Office of Academic Affairs-WUH.
SEND TO:
Office of Academic Affairs
Winthrop-University Hospital
259 First Street
Mineola, NY 11501

Re: Sarafidis PA, Bakris GL. Do the metabolic effects of β blockers make them leading or support-
ing antihypertensive agents in the treatment of hypertension? J Clin Hypertens (Greenwich).
2006;8:351–356.

Name:___________________________________________________________________________

Address: _________________________________________________________________________

________________________________________________________________________________

________________________________________________________________________________

358 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 5 MAY 2006

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions
and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at
showell@lejacq.com or 203.656.1711 x106.