Efficacy of Ivabradine, a Selective I_f Inhibitor, in Patients With Chronic Stable Angina Pectoris and Diabetes Mellitus

Article Outline

• Abstract
• Methods
• Results
• Discussion
• References
• Copyright

Ivabradine is a specific heart rate-lowering antianginal agent that was evaluated in a clinical development program involving approximately 3,000 patients with stable coronary artery disease, most with angina pectoris. We analyzed the pharmacokinetics, efficacy (evaluated by exercise tolerance testing), safety, and effects on glucose metabolism of ivabradine in patients with diabetes mellitus (DM) in this program. Most analyses included data from 535 patients with DM, approximately 18% of the overall patient sample. Patients with DM were older, more likely to be women, and more likely to have more severe angina pectoris than patients without DM. The pharmacokinetics of ivabradine did not differ in patients with DM versus those without DM. A reduction in the heart rate at rest with ivabradine was similar in those with (15.2%) and without (15.7%) DM. At baseline, the exercise capacity tended to be lower in the patients with DM, but the improvements in most exercise tolerance measures with ivabradine treatment were similar in patients with and without DM. No special safety concerns were associated with ivabradine in those with DM. The rates of sinus bradycardia and visual disturbances, known to be related to the action of ivabradine, showed no relative increase in the patients with DM. Ivabradine treatment was not associated with adverse effects on glucose metabolism. In conclusion, ivabradine was effective in preventing angina in patients with DM and was not associated with particular safety concerns or adverse effects on glucose metabolism. Ivabradine represents an attractive alternative to β blockers in patients with stable angina pectoris and DM.

Ivabradine is a specific heart rate-lowering antianginal agent that inhibits the I_f current, the primary modulator of spontaneous diastolic depolarization (the pacemaker current) in the sinoatrial node.¹ At therapeutic concentrations, ivabradine has no appreciable action on other cardiac or vascular ion channels and has no direct effects on myocardial contractility, intracardiac conduction, or ventricular repolarization in humans.², ³, ⁴ The antianginal and antimyocardial-ischemic efficacy of ivabradine has been demonstrated in randomized, controlled clinical trials⁵, ⁶, ⁷ and is not inferior to the β blocker atenolol⁶ or the calcium channel blocker amlodipine.⁷ Ivabradine is now recommended in European guidelines for the prevention of stable angina pectoris.⁸ The efficacy and safety of ivabradine were evaluated in a clinical development program that involved approximately 3,000 ivabradine-treated patients with stable coronary artery disease (CAD), more than 90% with angina. However, the drug's effects specifically in patients with diabetes mellitus (DM) have not been reported. The present analysis assessed the pharmacokinetics, efficacy, and effects on glucose metabolism of ivabradine in patients with DM, drawn from the data in the clinical development program.

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Methods 

Data were drawn from the 8 multicenter, randomized, double-blind, controlled trials designed to assess the efficacy and safety of ivabradine during its clinical development before regulatory approval in Europe (Table 1). In the large efficacy and safety studies (studies 1 to 6), male or female outpatients with chronic stable angina pectoris and documented CAD were treated for ≥3 months. The exclusion criteria included important heart disease other than CAD, Prinzmetal's or microvascular angina, known high-grade left main CAD, New York Heart Association class III or IV heart failure, atrial fibrillation or flutter, pacemaker or implanted defibrillator, second- or third-degree atrioventricular block, heart rate at rest <50 beats/min or sick sinus syndrome, and symptomatic hypotension or uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg). For the efficacy studies (studies 1 to 4), the patients were required to have 2 symptom-limited exercise tolerance tests (ETTs) with positive findings showing relative stability for the time to the onset of myocardial ischemia (1-mm ST-segment depression). In study 7, patients were required to have documented CAD and to have been treated for congestive heart failure, New York Heart Association class II, for ≥6 months, with a left ventricular ejection fraction of 30% to 45%. In study 8, patients were required to have documented CAD, but angina was not required for inclusion. The DM subgroup in each analysis included all patients with a medical history of DM of any type and severity, as reported by the investigator.

Table 1. Studies on which efficacy analyses were based

CAD = coronary artery disease; CHF = congestive heart failure; ETT = exercise tolerance test.

In all studies, the use of short-acting nitrates for angina relief was permitted as required; however, the ETT could not be performed within 2 hours of the patient taking nitrates. In the efficacy studies, drugs that could prevent angina were not permitted, including β blockers, calcium channel blockers, long-acting nitrates, potassium channel openers, molsidomine, and trimetazidine (except if mandated by the study protocol as active comparators or as background therapy). Drugs that could affect the interpretation of the electrocardiographic changes were also precluded, including antiarrhythmic agents, digitalis, amiodarone, and monoamine oxidase inhibitors. A wider range of drugs was permitted in the safety studies. Most drugs were allowed, with the exception of agents that alter the heart rate, including β blockers and nondihydropyridine calcium channel blockers, and drugs with known or suspected interactions with ivabradine, including antifungal azole derivatives and macrolide antibiotics or protocol-mandated comparator drugs.

All patients gave written informed consent, and the study protocols were reviewed by the relevant independent ethics committees. The studies were conducted in accordance with the principles of the Declaration of Helsinki, 1964, and later amendments.

In the efficacy studies, exercise capacity was evaluated by either treadmill or bicycle ETTs (Table 1) with 12-lead electrocardiographic recording (for details, see Borer et al⁵, Tardif et al,⁶ and Ruzyllo et al⁷). In the treadmill ETT (studies 2 and 3), a modified Bruce protocol was used. When bicycle ergometry was used, the initial workload was 30 W, increased by 30 W every 2 minutes (study 1), or 40 W increased by 10 W every minute (study 4). The ETT parameters of total exercise duration, interval to 1-mm ST-segment depression, and interval to angina onset were recorded. The electrocardiographic printouts were read at a central core facility by physicians unaware of the treatment allocation and patient identification. The heart rate at rest was measured by electrocardiography at the study visits. All patients kept a weekly angina diary from which the frequency of angina attacks was calculated. In all studies, timed blood samples were taken from a subset of ivabradine-treated patients for pharmacokinetic analysis of ivabradine and its active metabolite, S 18982. Blood concentrations of hemoglobin A1c and fasting blood glucose were determined from blood samples taken at baseline and at the end of treatment from patients with DM treated with ivabradine and comparator drugs.

The data from the different studies were pooled when appropriate. Data relating to changes in the heart rate at rest and angina attack frequency were collected using similar methods in several studies; these data were pooled. However, different ETT procedures were used in the main efficacy studies. Because bicycle ETTs can yield smaller apparent treatment effects than treadmill ETTs, the ETT results and exercise heart rate variations across the studies could not be pooled. The data from 2 large studies, in which ivabradine was given as monotherapy and compared with the β blocker atenolol using treadmill ETTs (study 2) and with the dihydropyridine calcium channel blocker amlodipine using bicycle ETTs (study 4), are presented individually.

Pharmacokinetic analyses were performed in a subset of patients in all studies from whom blood samples were available. The maximum drug concentration and area under the curve for ivabradine and its active metabolite, S 18982, were determined for each patient, normalized to an ivabradine dose of 5 mg twice daily, and pooled for comparison of patients with and without DM.

All patients with DM with evaluable data were included in the analysis of blood concentrations of hemoglobin A1c and fasting glucose, and the data were pooled across studies. The changes from baseline with treatment were compared between ivabradine and the comparator drugs atenolol and amlodipine.

All analyses for the present study were performed post hoc and were not planned in the original study protocols. Statistical significance testing, when performed, was done using Student's t test (unpaired) and should be considered exploratory.

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Results 

Patients with DM were approximately 18% of the total patient sample. Thus, the analyses of efficacy and heart rate changes were done using data from 535 patients with and 2,372 patients without DM treated with ivabradine. However, the number of patients varied for the different analyses, depending on data availability. For example, the pharmacokinetic analysis, for which only a subset of patients was tested, involved 788 patients treated with ivabradine (146 with DM). The baseline demographic and clinical characteristics of patients in the pooled sample used for the analyses of the efficacy and heart rate changes are listed in Table 2. Of the ivabradine-treated patients, those with DM were slightly older, a greater proportion were women, and a greater proportion had relatively severe (Canadian Cardiovascular Society grade III) angina compared with the patients without DM. Far fewer patients were treated with comparator drugs than with ivabradine. Therefore, the statistical estimates of differences between the patients with and without DM in the comparator groups were less precise than those for ivabradine-treated patients.

Table 2. Baseline demographic and clinical characteristics

Characteristic	No DM			DM
	Ivabradine (n=2372)	Atenolol (n=352)	Amlodipine (n=355)	Ivabradine (n=535)	Atenolol (n=83)	Amlodipine (n=49)
Mean age (years)	59.9±9.0	60.6±8.8	59.7±9.1	61.5±8.2	61.2±7.9	62.1±7.4
Gender
Male	85%	82%	87%	77%	80%	82%
Female	16%	19%	13%	23%	21%	18%
Coronary artery disease history
Myocardial infarction	52%	54%	45%	54%	47%	49%
Coronary artery bypass	18%	18%	13%	17%	25%	20%
Angioplasty	16%	18%	11%	20%	23%	14%
Anginal pain grade⁎
Grade I	21%	25%	11%	15%	22%	12%
Grade II	66%	66%	73%	65%	65%	67%
Grade III	13%	9%	16%	17%	10%	20%
Grade IV	0	0	0	0.2%	0	0

Data are presented as mean ± SD or percentages.

DM = diabetes mellitus.

Ivabradine is eliminated with a half-life of 2 hours for the primary compound in plasma; the effective half-life for ivabradine and its active metabolite, S 18,982, is 11 hours. The mean plasma maximum drug concentration and area under the curve values for ivabradine and S 18982 were similar between the DM subset and the overall pharmacokinetic patient sample (Figure 1), suggesting no obvious differences in the absorption, metabolism, and excretion of ivabradine in patients with DM.

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• Figure 1. 

  Main pharmacokinetic parameters for ivabradine and its active metabolite, S 18982, in patients with DM and overall pharmacokinetic patient sample. (Upper) Maximum drug concentration (Cmax) and (Lower) area under curve (AUC).

The changes in the heart rate at rest after treatment with ivabradine and atenolol (all doses pooled) in patients with and without DM are summarized in Table 3. At baseline, in the ivabradine group, the heart rate in those with DM was greater than in those without DM but the reduction in the heart rate with ivabradine treatment was similar in both groups. Similar results were seen in atenolol-treated patients.

Table 3. Heart rate reduction in patients without and with diabetes mellitus (DM) treated with ivabradine and atenolol (all doses pooled)

Diabetes Mellitus	Patients (n)	Heart Rate at Baseline (beats/min)	Change From Baseline (beats/min)
No
Ivabradine	2231	71.9±11.9	−11.3±11.1(−15%)
Atenolol	333	71.8±12.2	−12.1±11.3(−17%)
Yes
Ivabradine	501	76.5±12.8	−11.6±11.5(−15%)
Atenolol	80	76.7±14.0	−13.5±12.6(−18%)

Data are presented as mean ± SD, unless stated otherwise.

As noted, the ETT results for the 2 large efficacy studies (studies 2 and 4) of ivabradine as monotherapy are presented separately. In study 2 (treadmill ETTs), among those in the ivabradine group, the baseline values of the ETT parameters were all lower in the patients with DM relative to those without DM (Table 4). However, the antianginal and anti-ischemic efficacy of ivabradine was proportionately similar in both groups. The results in the patients with DM were similar for ivabradine and atenolol (Table 4). In study 4 (bicycle ETTs), all ETT parameters at baseline again were lower in those with DM compared with those without DM (Table 5). Improvements in the ETT parameters with treatment were smaller in study 4 than in study 2 for all ETT parameters and for both ivabradine and the comparator drug, amlodipine. Improvements with treatment were similar in patients with and without DM for the parameters time to 1-mm ST segment depression and time to angina onset. Improvements in total exercise duration were smaller among those with DM than among those without DM in both the ivabradine and the amlodipine treatment groups; however, the results in the patients with DM were similar with ivabradine and amlodipine for all ETT parameters.

Table 4. Exercise tolerance test (ETT) (treadmill, modified Bruce protocol) results for patients with and without diabetes mellitus (DM) in study 2

Variable	Patients (n)	Baseline (s)	Change From Baseline (s)
Total exercise duration
No diabetes mellitus
Ivabradine, all doses	475	602.9±128.3	92.1±124.0(15%)
Atenolol 100 mg once daily	224	573.6±146.7	75.0±132.4(13%)
Diabetes mellitus
Ivabradine, all doses	123	554.1±150.5	77.9±123.7(14%)
Atenolol 100 mg once daily	62	595.2±134.8	92.6±137.3(16%)
Time to 1-mm ST-segment depression
No diabetes mellitus
Ivabradine, all doses	471	541.0±158.4	93.5±139.2(17%)
Atenolol 100 mg once daily	224	507.9±153.9	94.0±143.7(19%)
Diabetes mellitus
Ivabradine, all doses	123	464.6±166.6	88.5±150.5(19%)
Atenolol 100 mg once daily	62	521.2±164.3	101.3±161.8(19%)
Time to angina onset
No diabetes mellitus
Ivabradine, all doses	474	482.1±146.8	145.9±150.8(30%)
Atenolol 100 mg once daily	223	454.5±147.8	131.6±152.4(29%)
Diabetes mellitus
Ivabradine, all doses	123	435.0±144.3	129.1±131.1(30%)
Atenolol 100 mg once daily	62	468.0±135.2	148.1±163.1(32%)

Data are presented as mean ± SD, unless stated otherwise.

Table 5. Exercise tolerance test (ETT) (bicycle) results for patients with and without diabetes mellitus (DM) in study 4

Variable	Patients (n)	Baseline (s)	Change From Baseline (s)
Total exercise duration
No diabetes mellitus
Ivabradine, all doses	660	422.7±137.9	26.4±94.3(6.2%)
Amlodipine 10 mg once daily	349	401.1±131.2	33.8±89.6(8.4%)
Diabetes mellitus
Ivabradine, all doses	97	393.4±135.0	13.2±84.1(3.4%)
Amlodipine 10 mg once daily	49	392.7±137.8	12.3±106.7(3.1%)
Time to 1 mm ST segment depression
No diabetes mellitus
Ivabradine, all doses	659	365.7±127.6	40.1±103.8(11%)
Amlodipine 10 mg once daily	347	349.1±122.7	40.6±103.4(12%)
Diabetes mellitus
Ivabradine, all doses	97	328.5±116.5	37.8±86.0(12%)
Amlodipine 10 mg once daily	49	335.2±132.8	33.2±102.3(9.9%)
Time to angina onset
No diabetes mellitus
Ivabradine, all doses	660	332.7±123.5	62.4±108.3(19%)
Amlodipine 10 mg once daily	349	314.1±121.3	68.0±99.2(22%)
Diabetes mellitus
Ivabradine, all doses	97	298.1±113.5	1.0±104.6(21%)
Amlodipine 10 mg once daily	49	305.1±126.1	56.2±99.0(18%)

Data are presented as mean ± SD, unless stated otherwise.

Among the ivabradine-treated patients, the frequency of angina attacks at baseline was slightly lower in those with DM than in those without DM (Table 6). However, ivabradine treatment reduced the angina attack frequency similarly, by more than 1/2, in patients with and without DM.

Table 6. Changes in frequency of angina attacks in patients with and without diabetes mellitus (DM)

Variable	Patients (n)	Baseline (attacks/wk)	Change From Baseline (attacks/wk)
No diabetes mellitus
Ivabradine, all doses	1968	3.7±6.1	−2.2±4.6(−60%)
Atenolol 100 mg once daily	318	3.5±14.0	−2.5±11.8(−71%)
Amlodipine 10 mg once daily	349	5.0±7.7	−3.0±5.8(−60%)
Diabetes mellitus
Ivabradine, all doses	457	3.3±5.9	−2.0±4.8(−61%)
Atenolol 100 mg once daily	78	2.4±4.0	−1.6±3.5(−67%)
Amlodipine 10 mg once daily	49	5.2±8.7	−3.3±7.0(−64%)

The safety of ivabradine treatment was assessed primarily in an analysis involving 2,907 ivabradine-treated patients with a mean duration of treatment of 146 days. Of these patients, 535 had DM. The proportion of patients withdrawn from treatment because of emergent adverse events tended to be slightly greater among patients with DM (8.6%) than among patients without DM (7.8%); the same was true for withdrawal because of cardiac disorders (4.7% in the DM vs 4.2% in the non-DM group). However, the patients with DM were older and had greater disease severity than did the patients without DM, although the differences between the groups were not significant. Withdrawals specifically because of unstable angina were similar in the 2 groups (DM 0.9%, overall population 0.8%); withdrawals because of myocardial infarction tended to be lower among those with DM (0.2%) than among those without DM (0.5%, p = NS).

Two specific adverse events are known to be related to the pharmacologic actions of ivabradine: sinus bradycardia, caused by the drug's heart rate-lowering action, and transient visual disturbances (known as phosphenes), possibly due to action on the retinal ion channels similar to those responsible for the I_f current in the sinoatrial node. The incidence of these adverse events was similar among those with and without DM (sinus bradycardia 3.7% among those with DM and 5.0% among those without DM, p = NS; visual disturbances 17.8% of those with DM and 21.8% of those without DM; p = NS). Among those with DM, visual disturbances led to treatment withdrawal in only 3 patients (0.6%).

The fasting blood glucose and hemoglobin A1c concentrations at baseline were similar in those with DM in the ivabradine, atenolol, and amlodipine treatment groups. In the ivabradine group, both the fasting glucose and the hemoglobin A1c levels nominally decreased slightly with treatment (Figure 2). In contrast, in patients who received atenolol and amlodipine, the fasting glucose and hemoglobin A1c levels nominally increased. The changes in hemoglobin A1c were significantly different between the ivabradine and atenolol (p = 0.049) and between the ivabradine and amlodipine (p <0.001) subgroups.

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• Figure 2. 

  Changes in glycemic parameters with treatment in patients with DM. (Upper) Glycosylated hemoglobin (HbA1c) in patients treated with ivabradine (n = 387), atenolol (n = 69), or amlodipine (n = 41). (Lower) Fasting glucose levels in patients treated with ivabradine (n = 492), atenolol (n = 76), or amlodipine (n = 49).

The pattern of changes in the fasting blood glucose level was similar to that observed for hemoglobin A1c (Figure 2). In patients treated with ivabradine, the fasting blood glucose nominally decreased, but it nominally increased in patients treated with atenolol and amlodipine. However, the between-group differences for fasting blood glucose only reached statistical trends (p = 0.074 for ivabradine vs atenolol and p = 0.069 for ivabradine vs amlodipine).

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Discussion 

These analyses have indicated, first, that DM does not affect plasma exposure to ivabradine and its active metabolite as measured by the pharmacokinetic parameters maximum drug concentration_. and area under the curve, although it should be noted that patients with severe hepatic and renal failure were excluded in these studies. Second, our data have suggested that DM does not affect the heart rate-lowering effect of ivabradine. Third, DM also does not have a negative effect on the antianginal efficacy of ivabradine, in terms of improvements in the ETT parameters and reductions in the frequency of angina attacks during patients' daily lives. Finally, ivabradine treatment in the patients with DM does not appear to cause any adverse effect on glycemic profiles, in terms of the fasting blood glucose and hemoglobin A1c concentrations. The hemoglobin A1c levels were lower in patients treated with ivabradine than in those treated with the comparator drugs atenolol and amlodipine.

Ivabradine selectively inhibits the I_f current, the primary modulator of spontaneous diastolic depolarization (the pacemaker current) in the sinoatrial node.¹ At therapeutic concentrations, ivabradine has no appreciable action on other cardiac or vascular ion channels and has no direct effects on myocardial contractility, intracardiac conduction, or ventricular repolarization in humans.², ³, ⁴ The antianginal and anti-ischemic efficacy of ivabradine has been demonstrated in randomized, controlled clinical trials⁵, ⁶, ⁷ and is not inferior to that of the β blocker atenolol⁶ and the calcium channel blocker amlodipine.⁷ The effect of ivabradine on outcome has been evaluated in the recent morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with CAD and left ventricULar dysfunction (BEAUTIFUL) study of 10,917 patients with CAD and left ventricular dysfunction. In patients with a baseline heart rate of ≥70 beats/min, ivabradine reduced the incidence of myocardial infarction (fatal and nonfatal) by 36%, the need for hospitalization for coronary events by 22%, and coronary revascularization by 30%.⁹ Recent data have also indicated that ivabradine can be used safely in patients taking β blockers⁹, ¹⁰; β blockers were routinely administered in most (87%) patients who received ivabradine in the BEAUTIFUL study. When co-administered with β blockers, ivabradine can confer additional antianginal efficacy.¹⁰

The effect of ivabradine on DM is important. Recent National Health and Nutrition Examination Survey (NHANES) data have suggested that 6.5% of United States adults have been diagnosed with DM and an additional 2.8% have undiagnosed DM.¹¹ The prevalence of DM increases steeply with age, reaching 18.3% to 21.6% in persons aged ≥65 years in the United States.¹¹, ¹² Approximately 18% of our study population (mean age 60 years) had DM, consistent with these estimates. It has been predicted that the prevalence of DM in the United States will double by 2050, largely owing to the increasing population age, improved survival among those with DM, and increasing obesity.¹² Thus, persons with DM will form a progressively larger subpopulation of those with stable angina.

Autonomic neuropathy is a common complication of even the early stages of DM.¹³, ¹⁴ Modulation of I_f in the sinoatrial node is one of the main mechanisms by which the autonomic nervous system regulates the heart rate.¹, ¹⁵ Thus, in theory, the heart rate-lowering action of ivabradine might be altered or diminished in patients with DM. Tachycardia at rest is a recognized manifestation of the cardiac autonomic neuropathy associated with DM,¹³ and the increased sympathetic tone and relatively rapid heart rate might accompany the obesity that is often linked with DM. In our analysis, the heart rate at rest at baseline was, on average, 4 to 5 beats/min greater in those with DM compared with those without DM. However, no difference was found in the heart rate-lowering effect of ivabradine (approximately 15%) between patients with and without DM. Because of the ion current/use dependence of ivabradine, the heart rate-reducing action of the drug is directly related to the pretherapy heart rate, limiting the likelihood of drug-induced symptomatic bradycardia. The relatively high heart rate at rest during middle age is associated statistically with the development of DM and DM-related mortality in older age patients.¹⁶

The anti-ischemic and antianginal efficacy of ivabradine, as evaluated by ETTs, was similar in patients with and without DM. At baseline, the ETT performance was generally lower in those with DM. However, the percentage of improvement in the ETT parameters with ivabradine was similar in patients with and without DM in all analyses but study 4, in which improvement in the total exercise duration was smaller for the patients with DM than for those without DM. Although the differential pain perception in patients with and without DM might have influenced this parameter in study 4,¹⁷ the ivabradine-mediated improvement in the time to 1-mm ST-segment depression, which does not depend on pain perception, was not reduced in those with DM, and the effects in those with DM of ivabradine and its comparator were similar.

No special safety concerns were present for using ivabradine in patients with DM. Importantly, the incidences of the 2 adverse events known to be related to the action of ivabradine, sinus bradycardia and visual disturbances, showed no tendency toward a relative increase in patients with DM. The relatively high incidence of visual disturbances (phosphenes) in both patients with and without DM might have been related to 2 methodologic factors. First, the analysis included patients receiving ivabradine doses higher (≤20 mg twice daily) than the recommended doses; and second, the patients were specifically questioned about visual disturbances at every study visit. In more recent studies, in which such leading questions were avoided, the incidence of phosphenes has been markedly lower. For example, in a recent 4-month study of patients with stable angina, the incidence was only 2.0% with ivabradine 7.5 mg twice daily compared with 0.9% with placebo.¹⁰

Patients with stable angina and DM have a markedly worse prognosis than corresponding patients without DM, after adjustment for a wide range of clinical variables.¹⁸ It is, therefore, important that the therapy for stable angina does not exacerbate existing DM or increase the incidence of new-onset DM. Several groups of cardiovascular drugs can have adverse effects on glucose metabolism, to the point that the term “drug-induced DM” has entered the clinical lexicon.¹⁹, ²⁰ Several studies of hypertensive patients have shown an increased risk of new-onset DM in patients treated with thiazide diuretics²¹ and β blockers.²², ²³ For example, during the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial of 19,257 patients,²³ treatment with atenolol (with the possible addition of a thiazide diuretic) was associated with a greater incidence of new-onset DM than was treatment with amlodipine (with or without perindopril), 799 versus 567 cases (p <0.0001).

β-Blocker therapy can reduce both insulin secretion and sensitivity to insulin in target tissues²⁴ and can lead to increases in blood glucose and hemoglobin A1c,²⁵, ²⁶ although these adverse metabolic effects might be less severe or absent with some adrenergic blockers such as carvedilol.²⁶ A specific heart rate-lowering agent such as ivabradine would be expected to cause minimal adverse metabolic effects; this prediction has been confirmed in the present analysis. No adverse changes were seen in the fasting glucose or hemoglobin A1c levels with ivabradine treatment, and the changes in the hemoglobin A1c levels were directionally and significantly different in patients treated with ivabradine compared with those treated with atenolol and amlodipine.

Although β blockers have been recommended as first-line treatment of stable angina,⁸, ²⁷ they are often not prescribed because of contraindications or intolerance, and many patients receive relatively low doses that often do not provide maximum β blockade or optimal therapy.²⁸ The results of the present analyses have indicated that ivabradine is effective in patients with DM and angina and is not associated with particular safety concerns or adverse effects on glucose metabolism in this population. Therefore, ivabradine represents an attractive alternative to β blockers in patients with stable angina and DM.

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References 

1. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Rev. 2006;53:399–406
   • View In Article
2. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R D. 2003;4:83–89
   • View In Article
   • MEDLINE
   • CrossRef
3. Manz M, Reuter M, Lauck G, Omran H, Jung W. A single dose of ivabradine, a novel I_(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100:149–155
   • View In Article
   • MEDLINE
   • CrossRef
4. Joannides R, Moore N, Iacob M, Compagnon P, Lerebours G, Menard JF, et al. Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise. Br J Clin Pharmacol. 2006;61:127–137
   • View In Article
   • MEDLINE
   • CrossRef
5. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an I_(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817–823
   • View In Article
   • CrossRef
6. Tardif J-C, Ford I, Tendera M, Bourassa MG, Fox K INITIATIVE Investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529–2536
   • View In Article
   • MEDLINE
   • CrossRef
7. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67:393–405
   • View In Article
   • MEDLINE
   • CrossRef
8. Fox K, Garcia MA, Ardessino D, Buszman P, Camici PG, Crea F, et al. Guidelines on the management of stable angina pectoris: executive summary. Eur Heart J. 2006;27:1341–1381
   • View In Article
   • MEDLINE
   • CrossRef
9. Fox K, Ford I, Steg PG, Tendera M, Ferrari M BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807–816
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   • Full-Text PDF (285 KB)
   • CrossRef
10. Tardif JC, Ponikowski P, Kahan T ASSOCIATE study investigators. Efficacy of the I_(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540–548
    • View In Article
    • CrossRef
11. Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Fiegal KM, Engelgau MM, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey 1999–2002. Diabetes Care. 2006;29:1263–1268
    • View In Article
    • MEDLINE
    • CrossRef
12. Narayan KM, Boyle JP, Geiss LS, Saadine JB, Thompson TJ. Impact of recent increase in incidence on future diabetes burden: U.A., 2005–2050. Diabetes Care. 2006;29:2114–2116
    • View In Article
    • MEDLINE
    • CrossRef
13. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553–1579
    • View In Article
    • MEDLINE
    • CrossRef
14. Schroeder EB, Chambless LE, Liao D, Prineas RJ, Evans GW, Rosamond WD, et al. Diabetes, glucose, insulin, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2005;28:668–674
    • View In Article
    • MEDLINE
    • CrossRef
15. Bucchi A, Baruscotti M, Robinson RB, DiFrancesco D. Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current. J Mol Cell Cardiol. 2007;43:39–48
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (884 KB)
    • CrossRef
16. Carnethon MR, Yan L, Greenland P, Garside DB, Dyer AR, Metzger B, et al. Resting heart rate in middle age and diabetes development in older age. Diabetes Care. 2008;31:335–339
    • View In Article
    • CrossRef
17. Ranjadayalan K, Umachandran V, Ambepityia G, Kopelman PG, Mills PG, Timmis AD. Prolonged anginal perceptual threshold in diabetes: effects on exercise capacity and myocardial ischemia. J Am Coll Cardiol. 1990;16:1120–1124
    • View In Article
    • Abstract
    • Full-Text PDF (304 KB)
    • CrossRef
18. Daly CA, De Stavola B, Lopez Sendon JL, Tavazzi L, Boersma E, Clemens F, et al. Predicting prognosis in stable angina—results from the Euro heart survey of stable angina: prospective observational study. BMJ. 2006;332:262–267
    • View In Article
    • CrossRef
19. Izzedine H, Launay-Vacher V, Deybach C, Bourry E, Barrou B, Deray G. Drug-induced diabetes mellitus. Expert Opin Drug Saf. 2005;4:1097–1109
    • View In Article
    • CrossRef
20. Blackburn DF, Wilson TW. Antihypertensive medications and blood sugar: theories and implications. Can J Cardiol. 2006;22:229–233
    • View In Article
    • Abstract
    • Full-Text PDF (187 KB)
    • CrossRef
21. Barzilay JI, Davis BR, Cutler JA, Pressel SL, Whelton PK, Basile J, et al. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–2201
    • View In Article
    • MEDLINE
    • CrossRef
22. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancatti FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study. N Engl J Med. 2000;342:905–912
    • View In Article
    • MEDLINE
    • CrossRef
23. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895–906
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (145 KB)
    • CrossRef
24. Pollare T, Lithell H, Selinus I, Berne C. Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ. 1989;298:1152–1157
    • View In Article
    • MEDLINE
    • CrossRef
25. Ostman J, Asplund K, Bystedt T, Dahlof B, Jern S, Kjellstrom T, et al. Comparison of effects of quinapril and metoprolol on glycaemic control, serum lipids, blood pressure, albuminuria and quality of life in non-insulin-dependent diabetes mellitus patients with hypertension. J Intern Med. 1998;244:95–107
    • View In Article
    • MEDLINE
    • CrossRef
26. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004;292:2227–2236
    • View In Article
    • CrossRef
27. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). www.acc.org/clinical/guidelines/stable/stable.pdf2002;Accessed February, 2008
    • View In Article
28. Carasso S, Markiewicz W. Medical treatment of patients with stable angina pectoris referred for coronary angiography: failure of treatment or failure to treat. Clin Cardiol. 2002;25:436–441
    • View In Article
    • MEDLINE
    • CrossRef