Med Clin N Am 88 (2004) 1037–1061
Ischemic heart disease and congestive heart failure in diabetic patients W.H. Wilson Tang, MDa,*, Anjli Maroo, MDa, James B. Young, MDb a
Department of Cardiovascular Medicine, Cleveland Clinic Foundation 9500 Euclid Avenue, Desk F25, Cleveland, OH 44195, USA b Department of Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F25, Cleveland, OH 44195, USA
Diabetes mellitus is a well-established independent risk factor for cardiovascular disease (CVD) in both men and women. The risk of CVD is increased 2 to 4-fold in patients with diabetes, and CVD contributes to more than 50% of deaths in this patient population [1]. The worldwide prevalence of diabetes is expected to double over the next 10 years, and concomitantly, the number of diabetic patients with ischemic heart disease or heart failure is expected to increase. Patients with impaired glucose tolerance or insulin resistance, which usually precede overt type 2 diabetes by several years, will add to the growing burden of cardiovascular disease, particularly in the younger population. Furthermore, diabetic patients with CVD suffer a worse long-term prognosis than their nondiabetic counterparts. In fact, the long-term mortality of diabetic patients without previously diagnosed CVD approaches that of nondiabetic individuals with a history of myocardial infarction (MI) (Fig. 1) [2]. Despite the complex metabolic interactions linking diabetes and CVD, these two disease processes are frequently diagnosed and managed separately by physicians in different subspecialties. This article summarizes our current understanding of ischemic heart disease and heart failure (HF) in patients with diabetes mellitus, highlighting gaps in our knowledge about the relationship between diabetes and CVD. Special consideration will be given to new strategies to treat the adverse effects of abnormal glucose metabolism on the cardiovascular system.
* Corresponding author. E-mail address:
[email protected] (W.H.W. Tang). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2004.04.008
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Survival (%)
80
60
40
Nondiabetic subjects without prior MI Diabetic subjects without prior MI Nondiabetic subjects with prior MI Diabetic subjects with prior MI
20
0 0
1
2
3
4
5
6
7
8
Year Fig. 1. Kaplan–Meier estimates of the probability of death from coronary heart disease in 1059 subjects with type 2 diabetes and 1378 nondiabetic subjects with and without previous myocardial infarction. I bars indicate 95% confidence intervals. Thin line, nondiabetic subject without prior MI; medium line, diabetic subjects without prior MI; gray line, nondiabetic subjects with prior MI; heavy line, diabetic subjects with prior MI. (From Haffner et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229, Ó Massachusetts Medical Society. All rights reserved; with permission.)
Pathophysiology Ischemic heart disease results from progressive or unstable coronary atherosclerosis. Atherosclerotic coronary artery disease in diabetic patients is often a diffuse process, affecting proximal and distal coronary segments. Diabetic patients frequently suffer from microvascular coronary disease and a reduction in vasodilatory reserve. Hyperinsulinemia and the insulin resistance syndrome are believed to have several adverse metabolic consequences that may promote atherogenesis [3–5]. For example, hyperinsulinemia may impair endothelial function by inhibition of nitric oxide synthesis and increased production of endothelin-1 [6]. Advanced glycosylation end products and elevated levels of free fatty acids, which are products of the hyperinsulinemic and hyperglycemic states, increase the production of reactive oxygen species, leading to increased oxidative stress and inflammation [7,8]. In addition, hyperglycemia is associated with an increase in chemoattractant cytokines and cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1, and intracellular cell adhesion molecule [9]. Diabetic patients are subject to a range of serum lipid abnormalities, including elevated levels of total cholesterol, very-low-density lipoprotein cholesterol, and triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol [10,11]. In diabetic patients, diminished activity of
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lipoprotein lipase leads to an accumulation of small, dense low-density lipoprotein (LDL) particles, which are prone to oxidative modification and uptake into macrophage-derived foam cells. These lipid abnormalities contribute to vascular injury and the development and progression of atherosclerotic lesions. Diabetes is associated with multiple perturbations of coagulation factors, platelet function, and inflammatory mediators that contribute to atherosclerotic plaque rupture and thrombosis formation (Box 1). Levels of the procoagulants fibrinogen, tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1, and factor VII are increased [12]. Levels of fasting insulin are inversely proportional to endogenous tissue plasminogen activator activity, resulting in an impairment of endogenous fibrinolysis in diabetic patients [13]. Platelets in diabetic individuals demonstrate increased aggregation and activation, with increased production of the potent platelet activator, thromboxane A2, and upregulation of the glycoprotein (GP) IIb/IIIa receptor [14–16]. Finally, elevated markers of inflammation, such as high sensitivity C-reactive protein and interleukin-6 have been associated with the development of both diabetes and atherosclerosis, although a common causal relationship remains to be proven [17,18]. Detection of asymptomatic ischemic heart disease in diabetic patients Despite an apparent lack of symptoms, the prevalence of transient asymptomatic ischemic episodes, or ‘‘silent’’ ischemia, approaches 10% to 15% in diabetic individuals, compared with 1% to 4% in their nondiabetic counterparts [19–21]. In some individuals, ischemic episodes are consistently asymptomatic; however, more commonly, ischemic episodes are an admixture of symptomatic and asymptomatic events. Our understanding of the mechanisms underlying silent ischemia is poor. Several theories have been proposed, including altered thresholds of pain sensitivity, autonomic neuropathy leading to sympathetic denervation, higher production of b-endorphins, and increased production of antiinflammatory cytokines [22–25]. Primary abnormalities of coronary blood Box 1. Selected thrombogenic risk factors in diabetes Endothelial dysfunction Platelet abnormalities Increased primary and secondary aggregation responses Increased release of a granule contents Increased thromboxane A2 production Coagulation abnormalities Increased plasminogen activator inhibitor (PAI-1) Increased fibrinogen
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flow reserve may mediate silent ischemic episodes, which occur primarily at rest or with minimal exertion [26]. The decision to perform screening in asymptomatic diabetic individuals is a difficult one because a lack of symptoms in the diabetic patient is not reassuring. Indeed, multiple studies [27,28] have shown that asymptomatic ischemia predicts multivessel coronary disease, increased adverse clinical outcomes, and poor survival. Nevertheless, there is a wide variability in risk profiles for CVD in diabetic patients. Because efforts to screen all diabetic individuals for CVD are not cost-effective, the American Diabetes Association and the American College of Cardiology/American Heart Association (ACC/AHA) have recommended screening diabetic patients at high risk for CVD who are about to embark on a moderate- to high-intensity exercise program. [29,30] ‘‘High risk’’ features are shown in Box 2. There are multiple modalities available for CVD screening. The reported accuracies of these tests in diabetic patients are shown in Table 1. The test most commonly used to screen for ischemia is the exercise treadmill test. The exercise treadmill test is easy to perform, relatively inexpensive, and is capable of generating several types of prognostic information, including ischemic ST– T wave abnormalities, exercise capacity, and heart rate recovery. The exercise treadmill test, however, is unable to localize ischemia and has diminished accuracy in the setting of baseline electrocardiograph abnormalities such as left ventricular hypertrophy, digoxin effect, resting ST-segment abnormalities, conduction abnormalities, and ventricular-paced rhythms. Stress myocardial perfusion imaging (eg, stress single photon emission computed tomography [SPECT]) can be used for risk stratification and diagnosis of CVD in patients with diabetes when the standard exercise treadmill test is inadequate. Several studies [31,32] have shown that SPECT has similar prognostic value in patients with and without diabetes. In symptomatic patients with diabetes, abnormalities on stress SPECT imaging independently predict the subsequent occurrence of cardiac death and MI [33]. Although data on the use of SPECT imaging in asymptomatic patients with diabetes are limited, preliminary studies have demonstrated that Box 2. Factors that increase risk for cardiovascular disease in diabetic patients
Age greater than 35 years old Type II diabetes of more than 10 years’ duration Type I diabetes of more than 15 years’ duration Any major cardiac risk factor Microvascular disease (proliferative retinopathy, nephropathy, microalbuminuria) Peripheral vascular disease Autonomic neuropathy
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Test
n
Symptomatic patients included?
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
Exercise tolerance testing [141] SPECT [31] Dobutamine stress echocardiography [142]
190
Yes
47
81
85
41
138 52
Yes Yes
86 82
56 54
89 84
48 50
abnormalities on stress SPECT imaging predict poor cardiovascular outcome [34]. A randomized multicenter study, the Detection of Ischemia in Asymptomatic Diabetics Trial (DIAD), is underway to help identify a high-risk group of patients with diabetes who may benefit from screening with SPECT stress imaging [35]. In addition, stress echocardiography has recently been shown to provide incremental prognostic information for risk stratification of diabetic patients with suspected CVD, compared with clinical and exercise test variables [36]; however, the application of stress echocardiography for screening asymptomatic patients with diabetes awaits further study. Electron beam computed tomography (EBCT) has emerged as a new technology to detect and quantitate coronary artery calcium deposits. The presence of coronary artery calcification, a product of atherosclerotic plaque formation, is always abnormal. EBCT allows measurement of the coronary calcium area and density and the calculation of a ‘‘coronary calcium score,’’ which serves as a semiquantitative measure of coronary plaque burden. The current role of EBCT for screening asymptomatic diabetic individuals, however, is controversial. The prevalence of coronary artery calcium in asymptomatic diabetic adults is higher than in their nondiabetic counterparts [37]. A clear association has not been demonstrated between coronary calcium and future cardiovascular events in diabetic individuals. Currently, the ACC/ AHA guidelines do not recommend general screening with EBCT because it is unclear whether EBCT will provide incremental predictive value over traditional risk models, such as the Framingham risk score [38].
Diagnostic testing for the evaluation of symptomatic ischemic heart disease The evaluation of angina in diabetic patients begins with a careful history, physical examination, and electrocardiogram. Further risk stratification can be performed using the stress test modalities described in the previous section. Theoretically, the pretest probability of disease in symptomatic diabetic patients should be higher than the pretest probability of disease in asymptomatic diabetic patients and in symptomatic nondiabetic patients.
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Coronary angiography is considered the gold standard test for the diagnosis of CVD and is recommended in patients with poorly controlled or new-onset angina or in patients with abnormal or high-risk noninvasive test results. In addition, coronary angiography is indicated in diabetic patients with multiple risk factors and a high clinical suspicion of coronary artery disease, despite ‘‘normal’’ noninvasive test results [39]. Diabetic patients with renal insufficiency warrant special consideration before angiography. The risks of progressive renal failure and dialysis should be clearly explained to the patient. Measures to prevent renal failure include adequate peri-procedural hydration, peri-procedural administration of N-acetylcysteine, sparing use of low osmolar, nonionic contrast, and the use of biplane imaging. Diabetic patients who take metformin are at risk for lactic acidosis after catheterization [40,41]. Metformin should be withheld on the day prior to and 2 days after the procedure to reduce the risk of lactic acidosis. Insulin and oral hypoglycemic medications should be withheld on the morning of the procedure to prevent hypoglycemia.
Medical therapy for ischemic heart disease in the diabetic patient Medications play an integral role in the management of anginal symptoms and the prevention of progression of atherosclerosis (Table 2). Nitrates are first-line antianginal agents that decrease myocardial oxygen demand by reducing preload and afterload and increase myocardial oxygen supply by vasodilatation of the coronary arteries. Chronic therapy is associated with nitrate tolerance, a phenomenon that may be increased in patients with diabetes because of impaired endothelium-dependent vasodilation [42,43]. For this reason, many patients observe a 12- to 14-hour nitrate-free period. Aspirin is an antiplatelet agent that irreversibly inhibits cyclooxygenase, resulting in inhibition of thromboxane synthesis and platelet aggregation. An aspirin (81–325 mg/d) is the recommended therapy for secondary prevention of CVD in all diabetic patients with a history of angina, MI, vascular revascularization procedure, stroke or transient ischemic attack, peripheral vascular disease, or claudication [44]. This recommendation is based on two large meta-analyses of major secondary prevention trials, performed by the Antithrombotic Trialists’ Collaboration [45,46]. These trials, which included 4502 patients with diabetes, demonstrated prevention of 38 vascular events for every 1000 diabetic patients treated with aspirin. In addition, the American Diabetes Association recommends low-dose aspirin therapy for primary prevention of CVD in all diabetic patients at high risk for CVD. Factors that confer high risk include: family history of coronary heart disease, cigarette smoking, hypertension, weight greater than 120% of ideal body weight, microalbuminuria or macro albuminuria, dyslipidemia (total cholesterol 200 mg/dL, LDL cholesterol 100 mg/dL, HDL cholesterol 55 mg/dL in women and 45 mg/dL in men, or triglyceride level 200) [44].
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Table 2 Medical therapies for ischemic heart disease Drug
Starting dosage
Major side effects
0.3–0.4 mg 10 mg 3 times/d/ 30 mg 4 times/da 0.2 mg/h
Headache, lightheadedness, flushing, orthostasis
25 mg 4 times/d 25 mg 2 times/d 25 mg 4 times/d then 2 times/d 40 mg 2 times/d then 4 times/d
Bradycardia, atrioventricular block, heart failure, fatigue, depression, erectile dysfunction, exacerbation of claudication, bronchospasm, increased insulin induced hypoglycemia
80 mg 4 times/d/ 240 mg 4 times/da 5 mg 4 times/d 20 mg 4 times/d 60 mg 4 times/d/ 240 mg 4 times/da
Bradycardia, atrioventricular block, heart failure, flushing, headache, constipation, pedal edema
ACE inhibitors Captopril Enalapril Lisinopril Ramipril
6.25–12.5 mg 3 times/d 2.5–5 mg 4 times/d 2.5–5 mg 4 times/d 1.25–2.5 mg 4 times/d
Hypotension, renal insufficiency, hyperkalemia, cough, angioneurotic edema, anaphylaxis
Aspirin
81–325 mg 4 times/d
Gastrointestinal ulcers, renal dysfunction, bronchospasm, rash
Clopidogrel
75 mg 4 times/d
Gastrointestinal ulcers, rash, thrombocytopenia, throbocytopenic thrombotic purpura (rare)
Nitrates Sublingual Oral Transdermal b-Blockers b1 Selective Metoprolol succinate Metoprolol tartrate Atenolol Nonselective Propranolol Calcium channel blockers Verapamil Amlodipine Nifedipine Diltiazem
a
Sustained release preparation.
The adenosine diphosphate (ADP) receptor antagonists ticlopidine and clopidogrel are thienopyridine agents that irreversibly block the binding of ADP to platelet type 2 purinergic receptors, thereby inhibiting ADPinduced platelet aggregation. Clopidogrel, 75 mg daily, is an acceptable alternative for patients with hypersensitivity or intolerance to aspirin. There is evidence that clopidogrel may be beneficial for prevention of recurrent CVD events in diabetic patients with a history of CVD. Clopidogrel was compared with aspirin for secondary prevention of CVD events in a randomized, controlled trial, the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study [47]. Overall, clopidogrel use was associated with an 8.7% relative risk reduction in the composite endpoint of vascular death, MI, or ischemic stroke. In the diabetes substudy
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of this trial, 3866 patients with diabetes were randomized to treatment with either clopidogrel or aspirin. After multivariable adjustment, clopidogrel was associated with a 13.1% relative risk reduction in the composite endpoint compared with aspirin (P = 0.032) [48]. Clopidogrel may also benefit patients presenting with acute ischemic heart disease (unstable angina or non–Q-wave MI). In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, the composite outcome of CV death, nonfatal MI, or stroke occurred in 9.3% of patients treated with a combination of clopidogrel plus aspirin, compared with 11.4% of patients treated with aspirin alone, after a mean of 9 months’ follow-up (P 0.001). A trend toward benefit with the combination therapy was maintained in the subgroup analysis of the 2840 diabetic patients in the trial (14.2% event rate in the combination group versus 16.7% in the group taking aspirin alone, P = not significant) [49]. As a result, updated guidelines from the ACC/AHA task force have recommended that clopidogrel be added to aspirin early in the treatment of patients presenting with unstable angina or non–Q-wave MI [50]. In clinical practice, the addition of clopidogrel is often deferred until after the patient’s cardiologist has chosen a revascularization strategy (percutaneous coronary intervention [PCI] versus coronary artery bypass graft surgery [CABG] versus medical therapy). Often, clopidogrel is not administered to patients who are scheduled to undergo CABG because of the recommendation that CABG be delayed for a minimum of 5 days after the last dose to prevent complications from bleeding. This recommendation is controversial, and several trials evaluating the optimal timing and dosage of clopidogrel administration are underway. GP IIb/IIIa inhibitors are intravenous antiplatelet drugs used during medical therapy for acute coronary syndromes or as adjunctive therapy during PCI. In the general population, the use of GP IIb/IIIa inhibitors has been associated with a reduction of up to 65 acute ischemic events per 1000 patients treated during elective and urgent PCI and with 15 to 32 events per 1000 patients treated for acute coronary syndromes [51]. One agent particularly, abciximab, has been associated with the long-term benefit of reduced mortality [52]. Several contemporary trials in PCI have shown that treatment with GP IIb/IIIa inhibitors is associated with a reduction in the combined 30-day endpoint of death, MI, and urgent revascularization in both diabetic and nondiabetic subpopulations [53]. It is presently unclear if the magnitude of benefit varies among the three available GP IIb/IIIa inhibitors. The effect of GP IIb/IIIa inhibitors on 6-month target vessel revascularization (TVR), a surrogate measure of clinical restenosis, is less certain. Rates of TVR varied markedly between trials and within the diabetic and nondiabetic subgroups. A substantial body of evidence has demonstrated that treatment with abciximab during PCI is associated with a marked reduction in 1-year mortality [52,54,55], a benefit that is particularly apparent for diabetic patients [56]. The benefit of GP IIb/IIIa
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inhibitors in non–ST-elevated MI has been demonstrated in a meta-analysis of six large randomized controlled trials [57]. In the 6458 diabetic patients enrolled in these trials, treatment with GP IIb/IIIa inhibitors was associated with a reduction in 30-day mortality from 6.2% to 4.6% (P = 0.007). Thus, the available data support the use of GP IIb/IIIa inhibitors in diabetic patients during PCI and during treatment of non–ST-elevated MI. b-Blockers (BBs) are powerful antianginal drugs that reduce myocardial demand by decreasing heart rate and cardiac contractility. BBs, however, have often been withheld in diabetic patients because of fears that these agents worsen insulin resistance, attenuate the warning symptoms of hypoglycemia, and worsen dyslipidemia. As experience with the use of BBs in patients with diabetes has accrued, these adverse effects have not proven to be common [58,59]. In the Bezafibrate Infarction Prevention (BIP) study, total mortality during a 3-year follow-up period was substantially reduced (7.8% versus 14.0%, BB versus no BB, respectively) in diabetic patients who received BBs, compared with those who did not. This reduction was demonstrated in diabetic patients with angina but without previous MI (3.9% versus 9.8%, BB versus no BB, respectively), as well as in diabetic patients with previous MI (9.7% versus 15.4%, BB versus no BB, respectively) [60]. Several landmark studies have demonstrated a reduction in reinfarction and an improvement in survival in patients who have already suffered an MI [61,62]. Despite convincing evidence that diabetic patients derive substantial benefit from b blockade, data from the National Cooperative Cardiovascular Project [63] have shown that diabetic patients are less likely to be discharged with a BB than nondiabetic patients following acute MI (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.88–0.99). Thus, further efforts to increase use of these medications in diabetic patients are warranted. Angiotensin converting enzyme (ACE) inhibitors have a well-established role in the early therapy of diabetic patients who have suffered an MI. One of the largest studies to address this question was the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardio (GISSI-3) trial [64]. This trial included 2790 diabetic patients in an open-label study of lisinopril, initiated during the first 24 hours of an MI. In the entire cohort (n = 18,895), treatment with lisinopril was associated with an 11% overall reduction in 6-week mortality compared with controls (6.3% versus 7.1%, OR 0.88, 95% CI 0.79–0.99). In the diabetic subgroup, treatment with lisinopril was associated with a 30% reduction in 6-week mortality (8.7% versus 12.4%, OR 0.68, 95% CI 0.53–0.86), which was maintained at 6month follow-up [65]. A recent systematic overview of four major randomized trials of early ACE inhibitor treatment following acute MI showed that early ACE inhibitor therapy was associated with a 7.1% 30-day mortality, compared with 7.6% in control subjects (7% proportional reduction; 95% CI 2%–11%) [66]. Diabetic patients showed a trend toward improved survival with ACE inhibitor therapy (30-day mortality, 10.3% in those treated with an ACE inhibitor versus 12.0% in control subjects). The
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absolute benefits of ACE inhibitor treatment were greater for diabetic versus nondiabetic patients (17.3 lives saved per 1000 versus 3.2 live saved per 1000, respectively). ACE inhibitor therapy is also beneficial in diabetic patients with at least one cardiovascular risk factor but no history of cardiovascular disease. The Heart Outcomes Prevention Evaluation (HOPE) study and the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO) HOPE substudy demonstrated that ramipril therapy was associated with a 25% reduction in the combined endpoint of MI, stroke, or cardiovascular death (95% CI 12–36, P = 0.0004) [67]. This benefit was seen irrespective of a history of cardiovascular disease. Additionally, recent results from the Efficacy of Perindopril in Reduction of Cardiovascular Events among Patients with Stable Coronary Artery Disease (EUROPA) study [68] demonstrate the benefit of ACE inhibitor therapy in diabetic patients with stable CVD. Calcium channel blockers (CCB) induce coronary and peripheral vasodilatation, decrease heart rate, and reduce cardiac contractility. As a group, CCBs are effective antianginal agents. Although CCBs are generally used in hypertensive diabetic patients who require multiple drugs for blood pressure control, CCBs may also be used for therapy of angina in the presence of contraindications or significant side effects to BBs [69]. In addition, CCBs may be added to BBs or nitrates if these drugs provide inadequate symptom relief. The dihydropyridine class of drugs (eg, amlodipine) produces more peripheral vasodilatation and less negative chronotropic and inotropic effects than CCBs such as diltiazem and verapamil. Use of short-acting CCBs (eg, nifedipine) is discouraged because of data suggesting an increased risk of MI [70,71]. On the other hand, CCBs are the treatment of choice for Prinzmetal’s (or variant) angina. In addition to pharmacotherapy for angina, diabetic patients with ischemic heart disease should undergo intensive cardiac risk factor modification to prevent progression of atherosclerosis. These therapies include treatment of hypertension (target blood pressure 130/85 mm Hg), lipid-lowering therapies (target LDL cholesterol 100 mg/dl, triglycerides 150 mg/dl, HDL 40 mg/dl), smoking cessation, glycemic control (target hemoglobin A1c 6.5%), and weight control. For patients with chronic stable angina that is refractory to conventional antianginal medications and CVD that is not amenable to further surgical or percutaneous revascularization, enhanced external counterpulsation is a mechanical therapeutic option that may provide symptom relief [72]. Coronary revascularization Despite maximal medical therapy, many diabetics require coronary artery revascularization, using methods such as percutaneous transluminal coronary angioplasty (PTCA), PCI with coronary stenting, or CABG for treatment of ischemic heart disease. It is clear that diabetic patients have a higher risk
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adverse outcomes following either percutaneous or surgical revascularization than nondiabetic patients [73–75]. According to the National Heart, Lung, and Blood Institute’s 1985–1986 PTCA registry, despite similar procedural success rates of balloon angioplasty, diabetic patients had a higher rate of inhospital death, MI, and emergent CABG, compared with nondiabetic patients (11% versus 6.7%, OR 1.74, P \ 0.001) and a lower rate of survival at 9-year follow-up (67.4% versus 83.9%, P \ 0.0001) [75]. In pooled analyses of PCI with coronary stenting, diabetic patients were found to have higher rates of death, MI, or repeat revascularization at 6 months or 1-year follow-up (21.1% versus 15.3%, OR 1.5%, 95%CI 1.3–1.7), compared with their nondiabetic counterparts [76]. Similarly, in a surgical series of CABG [74], diabetic patients had a higher incidence of postoperative death (3.9% versus 1.6%, P 0.05) and a lower 10-year survival (50% versus 71%, P 0.05), compared with nondiabetic patients [74]. The advent of coronary stent implantation has significantly improved the results of PCI, specifically by reducing the rate of restenosis and by decreasing the need for TVR [77–79]. In diabetic patients, although coronary stenting has improved outcomes compared with PTCA, diabetes remains an independent risk factor for adverse events, and diabetic patients continue to have a poorer prognosis than nondiabetic patients [80]. Intracoronary radiation may be used to treat in-stent restenosis in both diabetics and nondiabetics. Drug-eluting stents (eg, sirolimus and paclitaxel-eluting stents) have been associated with a marked reduction in the development of restenosis [81]. The preliminary results of the Sirolimus-Eluting Stent in Native Coronary Lesions (SIRIUS) trial demonstrated a significant improvement with the use of sirolimus-coated stents compared with bare metal stents, with respect to in-segment restenosis (8.9% versus 36.3%) and target lesion revascularization (4.1% versus 16.6%) [82]. In the recently presented TAXUS IV trial, the use of a paclitaxel-coated stent was associated with a reduction of target lesion revascularization from 11.3% to 3.0% (P \ 0.0001) and of in-stent binary restenosis from 24.4% to 5.5%, compared with bare metal stents. The composite endpoint of cardiac death, MI, or TVR was also reduced from 15.0% to 8.5% (P = 0.0002) [83]. The effects of drugeluting stents in the diabetic subpopulation are currently being evaluated. The optimal method of coronary revascularization (PTCA versus PCI with stenting versus CABG) has been a matter of long-standing debate. Initial data from two large randomized trials demonstrated a survival benefit in diabetic patients treated with CABG rather than PTCA for multivessel CVD [84,85]. This finding was supported by data from the landmark Bypass Angioplasty Revascularization Investigation (BARI) study [86]. In this study, the 5- and 7-year survival rates were similar between PTCA and CABG in the overall study population. In the diabetic subgroup (n = 353), however, 5- and 7-year survival rates were higher in the group assigned to CABG, compared with PTCA (5-year survival, 80.6% versus 65.5% [P = 0.003]; 7-year survival, 76.4% versus 55.7% [P=0.0011]) [87,88]. The results of the BARI
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randomized trial were not seen in the BARI registry, raising some questions about generalizing the results to diabetic patients outside of controlled clinical trials [89]. Two major trials, the Arterial Revascularization Therapies Study (ARTS) and Stent or Surgery (SOS) study, were designed to compare PCI with coronary stenting versus CABG [90,91]. Both trials found no significant difference in death or MI between the PCI and CABG groups in long-term follow-up; however, the need for repeat TVR was increased in the PCI groups compared with the CABG groups (21% versus 3.8% in ARTS, P \ 0.001). The diabetic patients in ARTS (n = 208) had a higher 1-year event-free survival with CABG, compared with PCI (84.4% versus 63.4%, P \ 0.001) [92]. Most of this difference resulted from the increased need for repeat TVR following PCI. Despite these data favoring selection of CABG in diabetic patients, advances in adjunctive therapies during PCI and the recent introduction of drug-eluting stents leave the question about the optimal revascularization strategy for diabetic patients unanswered. Further studies are ongoing to help guide clinical decision making. In addition, the BARI 2D study has been designed to evaluate strategies for glycemic control during revascularization [93]. Heart failure in diabetic patients: epidemiology HF is common in the diabetic population, with an overall prevalence of 12%, based on community-based studies [94]. Diabetes is present in 24% to 28% of patients enrolled in large-scale clinical trials of HF therapies [95–97]. Furthermore, diabetic patients constitute 25% to 30% of all patients hospitalized for HF [98,99]. Overall, the estimated incidence of developing symptomatic HF is 3.3% per 100 person-years [94]. This risk is increased 2.4-fold in diabetic men and 5-fold in diabetic women, compared with matched controls, independent of coexisting hypertension or ischemic heart disease [100]. According to the ACC/AHA HF guidelines, the presence of diabetes mellitus is regarded as stage A HF (patients at risk of HF) or stage B HF (patients with structural abnormalities such as left ventricular hypertrophy without overt cardiac dysfunction) [101]. Conversely, there is some evidence that HF may be an independent risk factor for the development of diabetes. In the BIP study, over a 7.7-year follow-up period, diabetes developed in 13% of patients with New York Heart Association (NYHA) class I HF, 15% with NYHA class II, and 20% with NYHA class III (P for trend = 0.05) [102]. In an elderly cohort of patients followed for 3 years, HF predicted development of noninsulin dependent diabetes independently of age, sex, family history of diabetes, body mass index, waist/hip ratio, systolic and diastolic blood pressure, and therapy for HF (OR = 1.4, 95% CI = 1.1–1.8) [103]. The association between HF and diabetes in this study became stronger as HF severity increased. Interestingly, the use of drugs such as losartan and carvedilol has been associated with
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a significant reduction in the incidence of new-onset diabetes mellitus in patients with HF, when compared with placebo [104,105]. Therefore, in addition to regular screening for diabetes (minimum every 3 years), strategies to prevent diabetes in patients with HF should be used whenever possible. Although the evidence is controversial, most experts acknowledge the existence of a distinct diabetic cardiomyopathy. Morphologic features associated with diabetic cardiomyopathy include myocyte hypertrophy, interstitial fibrosis, intramyocardial microangiopathy, and infiltration with periodic acid-Schiff-positive materials [106,107]. Many of these histologic findings, however, are nonspecific and are present in other forms of nonischemic cardiomyopathies. Population-based studies, such as the Framingham Heart Study and Strong Heart Study, have shown that in diabetic patients, characteristic echocardiographic structural and functional abnormalities such as increased left ventricular mass, wall thickness, and measures of diastolic dysfunction can precede overt HF by many years [108,109]. Recently, investigators have raised the possibility that plasma B-type natriuretic peptide (BNP) may be helpful in detecting early left ventricular dysfunction in diabetic patients [110], but this hypothesis requires further testing, and currently, plasma BNP is not recommended as a screening tool. The incidence of new-onset HF following acute coronary syndromes is at least 2 times higher in diabetic versus nondiabetic patients [111,112]. Heart failure may occur in up to 50% of diabetic patients who suffer an acute MI [113]. In addition, diabetic patients in the GUSTO IIb trial had increased mortality after MI, independent of the presence of ST elevation [114]. Stressinduced hyperglycemia during acute MI has been consistently shown to increase mortality, even in patients without a previous of diabetes [115]. The exact mechanisms underlying progression to HF in diabetic patients with acute MI are unclear. The development of HF may be independent of the initial degree of myocardial damage and of long-term ventricular remodeling. In the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study, diabetic patients with smaller infarct sizes (lower peak creatine phosphokinase levels, smaller areas under the curve of serial creatine phosphokinase measurements, and fewer new Q waves on serial electrocardiography) still had a worse prognosis compared with their nondiabetic peers (4-year cardiac mortality 25.9% versus 14.5%). In the Survival and Ventricular Enlargement (SAVE) echocardiographic substudy, the degree of left ventricular dilatation 2 years after MI was actually greater in nondiabetic compared with diabetic patients [116]. Furthermore, the development of left ventricular dilatation 2 years after MI did not predict subsequent HF in diabetic patients, even after multivariable adjustment. Management of heart failure in patients with diabetes Although the management of chronic heart failure in patients with diabetes mellitus follows the same general approach used to treat these two
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syndromes individually, special considerations should be given when using some HF drugs in the diabetic population (Table 3). Every effort should be made to maximize myocardial blood flow (either by percutaneous or surgical revascularization) in the failing heart to reverse the underlying, hibernating myocardium. Diuretic medications have been the mainstay of therapy for volume overload. Loop diuretics, the most commonly used diuretics, can be highly effective in both diabetic and nondiabetic patients; however, careful monitoring of serum electrolytes and renal function is required. Anecdotal observations have demonstrated that high-dose thiazide diuretics may impair insulin sensitivity [117]. These diuretics should be avoided unless clinically required. Use of spironolactone, a nonselective aldosterone antagonist and a weak diuretic, in patients with severe HF and left ventricular ejection fraction (LVEF) less than 35% conferred a 30% reduction in the risk of death, a 35% reduction in hospitalization for worsening HF, and a significant improvement in the symptoms of HF in the Randomized Aldactone Evaluation Study (RALES) [118]. Unlike other diuretics, spironolactone does not impair glucose tolerance. A selective aldosterone antagonist, eplerenone, was recently shown to reduce death from cardiovascular causes versus placebo in patients with post-MI HF (relative risk, 0.83, 95% CI 0.72– 0.94, P = 0.005) [119]. Although they demonstrate potential benefits in diabetic patients with advanced HF, these two drugs may substantially increase the risk of developing hyperkalemia and renal insufficiency and should be used with caution in the diabetic population [120]. ACE inhibitors (or angiotensin-II receptor antagonists for ACE-inhibitor intolerant patients) should be given at target doses to every diabetic patient with HF unless contraindicated. The evidence supporting their use was discussed previously. It should be noted that in addition to conferring a mortality reduction benefit in those with LV dysfunction, ACE inhibitors may increase insulin sensitivity in diabetic patients by affecting the early steps of insulin signaling [121]. Angiotensin II receptor blocker (ARB) drugs act selectively at the angiotensin II type (AT)1 receptor. Data on the benefit of ARBs in patients with HF have conflicted. In the Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, losartan use was not associated with a significant reduction in all-cause or cardiovascular mortality [122]. In the Valsartan Heart Failure Trial (Val-HeFT), there was no significant difference in overall mortality in diabetic patients treated with valsartan versus placebo [96]. In contrast, in the recently published Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials, candesartan use was associated with a reduction of less than 40% in the composite endpoint of cardiovascular death or hospital admission for HF versus placebo in patients with LVEF who were not receiving ACE inhibitors because of previous intolerance (unadjusted hazard ratio 0.77, 95% CI 0.67–0.89) and less than 40% in patients with LVEF who were receiving concurrent therapy with ACE inhibitors (unadjusted hazard ratio 0.85, 95%
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Table 3 Common heart failure drugs with special considerations for diabetic patients Drug class (examples) ACE inhibitors Captopril Enalapril Lisinopril Ramipril
b-Blockers Carvedilol Metoprolol succinate Bisoprolol Spironolactone
Hydralazine/ isosorbide dinitrate Diuretics Furosemide Bumetanide Torsemide Metolazone
Start dose (mg)
Target dose (mg)
Special considerations in diabetics
50 3 times/d 10 2 times/d 10–20 4 times/d 5 2 times/d
Indicated for all HF patients unless contraindicated (# blood pressure, "potassium, "creatinine (use hydralazine/ isosorbide dinitrate if creatinine 3 mg/dL, angioedema/cough)
3.125–6.25 12.5–25
25 2 times/d 100 4 times/d
2.5–5
20 4 times/d
Indicated for all systolic HF patients unless contraindicated (#pulse rate, #blood pressure, heart block, reactive airway disease)
6.25–12.5 2.5–5 2.5–5 1.25–2.5
12.5–25
25 3 times/d 10 4 times/d
20–40 1–2 1–10 2.5–5
N/A
Indicated for advanced systolic HF (NYHA class III-IV), need to closely watch for "potassium, "creatinine in diabetic patients; no need for up-titration
100 3 times/d 40 4 times/d
Indicated for ACE-inhibitor/ARBintolerant patients and those with advanced renal insufficiency
Titrate to euvolemia
Indicated for symptomatic relief from fluid retention; thiazides (but not loop diuretics) may attenuate insulin sensitivity
Digoxin
0.125
N/A
Indicated for advanced HF to prevent morbidity, particularly with concomitant atrial fibrillation; watch for toxicity especially with amiodarone and renal insufficiency; prefer a lower dose (0.125 4 times/d or 4 times every other day) especially in elderly and in women; no need for up-titration
ARBs Losartan Valsartan Candesartan
25 80 4
50 4 times/d 160 4 times/d 32 4 times/d
Indicated for ACE-inhibitor intolerant HF patients; appears to be beneficial when added to ACE-inhibitor in HF patients (CHARM) and possibly in CHF patients with preserved LVEF
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CI 0.75–0.96) [123,124]. Further analyses of the diabetic patients in these studies are pending, although preliminary evaluation of the nondiabetic patients in the CHARM trial demonstrated a reduction in new-onset diagnoses of diabetes in patients treated with candesartan. Overall, there has not been a consistent class-specific mortality benefit associated with ARBs. Nevertheless, ARBs definitely should be prescribed to patients who cannot tolerate ACE inhibitors. Furthermore, there may be a role for adding candesartan to ACE inhibitor therapy in patients who are able to tolerate the combination. BBs have been well tolerated and clearly effective in diabetic subgroups in large-scale HF trials. Historically, BBs were contraindicated in HF patients in general and in diabetic patients particularly because of adverse effects on insulin sensitivity and lipid profiles. Several contemporary studies, however, have firmly established the beneficial role of BBs in diabetic patients with HF, with respect to survival, improvement in LVEF, and reversal of left ventricular remodeling [125]. Moreover, the use of metoprolol succinate did not result in an increased incidence of diabetes, worsening glycemic control, or masking of hypoglycemic symptoms in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) [126]. The nonselective BB carvedilol is also well tolerated in diabetic patients [127], and in a recent randomized, controlled trial, the Carvedilol Or Metoprolol European Trial (COMET), all-cause mortality was lower with the use of carvedilol (25 mg twice per day), compared with metoprolol tartrate (50 mg twice a day) in patients with LVEF less than and NYHA Class II-IV HF [97]. Thus, BB therapy should be attempted in all diabetic patients with chronic stable HF. Digoxin should be limited to patients with symptomatic congestive HF or those with concomitant rapid atrial fibrillation. Although digoxin is effective in reducing symptoms of HF and decreasing the number of HF hospitalizations, it has not been shown to confer any mortality benefit, and digoxin toxicity is common in diabetic patients with concurrent renal insufficiency [128]. Given the multiple drug categories that are available for the treatment of chronic HF, care must be taken to avoid polypharmacy and drug-drug interactions. In the diabetic patient particularly, physicians must exercise vigilance to prevent disturbances in electrolytes and renal function and to maximize patient compliance with drug regimens. Although several drug classes can confer benefit in the diabetic patient with HF, tolerability of prescribed regimens is crucial to treating this multisystem disorder.
Glycemic control in diabetic patients with cardiovascular diseases Metabolic interventions are exciting new therapies that are particularly attractive for patients with diabetes. Metabolic intervention may improve
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myocardial performance in multiple settings, including stable ischemia, acute coronary syndromes, and chronic HF. In ischemia, metabolic perturbations may blunt the compensatory response of the diabetic myocardium. Perturbations include increased circulating plasma insulin, glucose, and fatty acid levels, in addition to decreased rates of glucose uptake, glycolysis, and myocardial pyruvate oxidation [129]. Therefore, one of the principal objectives of metabolic interventions is to decrease myocardial uptake and oxidation of free fatty acids and to increase myocardial uptake and use of glucose and lactate [130]. The Swedish Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study tested this concept by randomizing patients with suspected acute myocardial infarction to an infusion of glucose-insulinpotassium (GIK) plus standard medical therapy versus standard therapy alone [131]. The DIGAMI protocol used an insulin and glucose infusion for tight glycemic control for at least 24 hours during the acute event. This regimen was followed by treatment with subcutaneous insulin for the subsequent 3 months. At 1-year follow-up, mortality in the treatment group was 18.6%, compared with 26.1% in the control group, representing a 29% decrease in mortality with the use of GIK infusion. These results were maintained during long-term follow-up and confirmed in a recent metaanalysis of all trials on GIK infusion during acute MI [132]. In patients with chronic stable angina, two new classes of metabolic agents, the 3-ketoacyl-coenzyme A thiolase (3-KAT) inhibitors and the partial fatty acid oxidation (pFOX) inhibitors, have been used to treat symptoms of ischemic heart disease. Trimetazidine (a prototype 3-KAT inhibitor) and ranolazine (a prototype pFOX inhibitor) have been shown to improve exercise tolerance and alleviate anginal symptoms [133–135], but neither drug is currently available in the United States. Tight glycemic control is an essential component of the management of HF and ischemia. The UK Prospective Diabetes 35 study [136] showed that every 1% decrement in hemoglobin A1c level was associated with a 14% and 16% relative reduction in the risk of developing MI and HF, respectively. Many diabetic patients rely on oral hypoglycemic drugs, taken either alone or in combination with insulin, to maintain glycemic control; however, there is a paucity of information regarding the safety and efficacy or newer oral hypoglycemic drugs in diabetic patients with HF. Both the biguanides (eg, metformin) and the thiazolidinediones (TZDs) (eg, rosiglitazone and pioglitazone) are regarded as ‘‘relatively contraindicated’’ in diabetic patients with HF. Cases of fatal lactic acidosis were reported in patients with HF and diabetes who were treated with biguanides [137]. As a result, the use of metformin is relatively contraindicated in patients who have renal insufficiency (serum creatinine 1.5 mg/dL), baseline liver function test abnormalities, are elderly (age 80 years old), or who are taking medications for HF. There is also a concern that the use of thiazolidinediones may cause overt HF. Fluid retention, weight gain, and pulmonary edema have been reported in
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patients using TZDs [138–140]. The mechanism underlying this phenomenon is unclear, but TZD-related fluid retention is largely restricted to the periphery and is usually reversible with drug withdrawal [141]. These observations have led to the hypothesis that TZDs may cause altered vascular permeability leading to fluid retention. Because TZDs have multiple beneficial effects in diabetic patients, including improvement in glycemic control, lipid profile, and endothelial function, as well as amelioration of albuminuria and diabetic nephropathy, further clarification of the relationships among TZDs, fluid retention, and congestive HF will help physicians maximize the use of these drugs in appropriate patients [142]. Summary Ischemic heart disease and HF are major contributors to morbidity and mortality in patients with diabetes mellitus. Although we have made great progress in our understanding of the pathophysiology of cardiovascular disease and diabetes mellitus, cooperation between cardiologists, diabetologists, and internists is needed to optimize and balance therapies for these disorders. References [1] Laakso M, Lehto S. Epidemiology of risk factors for cardiovascular disease in diabetes and impaired glucose tolerance. Atherosclerosis 1998;137(Suppl):S65–73. [2] Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34. [3] Ruige JB, Assendelft WJ, Dekker JM, et al. Insulin and risk of cardiovascular disease: a meta-analysis. Circulation 1998;97:996–1001. [4] Stout RW. Insulin and atheroma. 20-yr perspective. Diabetes Care 1990;13:631–54. [5] Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952–7. [6] Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, et al. Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 2002;105:576–82. [7] Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP, et al. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 1998;37:586–600. [8] Evans JL, Goldfine ID, Maddux BA, Grodsky GM, et al. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003;52:1–8. [9] Marfella R, Esposito K, Giunta R, Coppola G, De Angelis L, Farzati B, et al. Circulating adhesion molecules in humans: role of hyperglycemia and hyperinsulinemia. Circulation 2000;101:2247–51. [10] Laakso M. Lipids and lipoproteins as risk factors for coronary heart disease in non-insulin-dependent diabetes mellitus. Ann Med 1996;28:341–5. [11] Syvanne M, Taskinen MR. Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes mellitus. Lancet 1997;350(Suppl 1):SI20–3.
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