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Heart Metab. (2015) 68:31-34case report

Up to 80% of diabetic patients die from cardio-vascular (CV) disease.1 Multiple factors (eg, hyperglycemia, a high level of low-density

lipoprotein (LDL) cholesterol, elevated blood pres-sure, and smoking) contribute to accelerate ath-erosclerosis. Yet, even after adjustment for all these factors, the relative risk of cardiac mortality remains 3 to 5 times higher in diabetics.2 For whatever reason, the atherosclerotic involvement in diabetic subjects

tends to be more severe and more diffuse than in nondiabetic subjects. Hyperglycemia, per se, exerts a deleterious effect on endothelial function and reduces coronary flow reserve beginning in the early stages of the disease. Studies on heart microcirculatory dysfunction in diabetes suggest that microvascular disease is systemic, occurring in the heart as well,3 where it contributes to poorer outcome upon coronary revascularization and more common heart failure.

Preventing cardiovascular events in diabetic patients: the case of the patient with poor distal coronary targets

Elisabetta Salutini, MD; Cristina Bianchi, MD; Roberto Miccoli, MD; Stefano Del Prato, MD, PhDDepartment of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases,

University of Pisa, Italy

Correspondence: Stefano Del Prato, MD, Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, Nuovo Ospedale Santa Chiara, Via Paradisa, 2, 56124 Pisa, Italy

E-mail: stefano.delprato@med.unipi.it

AbstractCardiovascular disease is a major cause of morbidity and mortality in diabetes. Hypoglycemia, a com-mon side effect of antidiabetic therapy, is associated with an increased risk for cardiovascular disease in diabetic patients and may precipitate angina in those with underlying myocardial ischemia. Thus, the prevention and prompt recognition of hypoglycemia is highly desirable in diabetic patients, especially in those with ischemic heart disease. Moreover, ischemia due to microvascular dysfunction is a frequent finding in people with diabetes. In that setting, in which surgical or percutaneous coronary intervention are not viable options, a rational use of antianginal therapy may help maximize the cardiometabolic benefits of treatment and improve quality of life. For example, trimetazidine can significantly ameliorate recurrent ischemia with a neutral or even favorable impact on glucose metabolism in diabetic patients. We present a clinical case that illustrates the importance and usefulness of a multidisciplinary approach when treating diabetic patients with ischemic cardiac disease. L Heart Metab. 2015;68:31-34

Keywords: coronary artery disease; diabetes; glucagon-like peptide-1 agonists; hypoglycemia; incretin; microvascular coronary dysfunction

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Case report

Miss AR is a 63-year-old diabetic woman who was referred to our diabetes center in March 2014. Her family history was positive for coronary artery disease (CAD). She quit smoking in 1993. Her medical his-tory was significant for hypertension, hypercholester-olemia, and obesity. She had type 2 diabetes mellitus (T2DM) for 13 years, complicated by nonproliferative retinopathy, but had preserved renal function and no signs of neuropathy. She was on olmesartan, aspi-rin, metformin, glibenclamide, and rosuvastatin. Her weight was 86 kg (body mass index, 30.5 kg/m2). Physical examination, blood pressure (135/80 mm Hg), and heart rate (70 bpm) were normal. Her fasting plasma glucose value was 5.5 mmol/L (99 mg/dL), glycated hemoglobin A1c (HbA1c) was 54 mmol/mol (7.1%), and LDL-cholesterol was 2.77 mmol/L (107 mg/dL). She complained of bouts of palpitations, confusion, and chest discomfort that usually resolved with ingestion of carbohydrates. Examination of her blood glucose monitoring revealed multiple values <3.9 mmol/L (70 mg/dL), particularly at times of un-predicted physical activity. Because of recurrent hy-poglycemic episodes and obesity, glibenclamide was withdrawn and liraglutide initiated at the dose of 0.6 mg daily, to be increased to 1.2 mg 10 days later. A cardiologic evaluation was also planned. Basal elec-trocardiogram (ECG) analysis (Figure 1) showed signs of altered reperfusion and a dipyridamole stress test was performed, which showed no signs of inducible myocardial ischemia. The rosuvastatin dose was in-creased to ensure attainment of target LDL choles-terol levels. Six months later, her HbA1c level was 47 mmol/mol (6.7%) with a 3-kg loss in body weight and no further episodes of hypoglycemia, though she still experi-enced chest discomfort during occasions of physical effort–associated dyspnea, which resolved spontane-

ously within 10 minutes. She underwent myocardial perfusion single-photon emission computed tomog-raphy (SPECT) (Figure 2), showing stress-inducible impairment of coronary blood flow reserve, whereas coronary angiography did not indicate significant epi-cardial coronary artery stenosis. Diltiazem was pre-scribed to which trimetazidine was then added with marked improvement.

Discussion

CAD is common in T2DM patients due to the con-comitance of multiple CV risk factors.4 The role of gly-

AbbreviationsCAD: coronary artery disease; CV: cardiovascular disease; ECG: electrocardiogram; ELIXA: Evaluation of LIXisenatide in Acute coronary syndrome; GLP-1: glucagon-like peptide-1; HbA1c: glycated hemoglobin A1c; LDL: low-density lipoprotein; SPECT: single-photon emission computed tomography; T2DM: type 2 dia-betes mellitus

I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

Fig. 1 Basal electrocardiogram: right bundle branch block, mild ST-segment depression with inverted T waves in aVF, DIII, V3-V4.

salutini and others Heart Metab. (2015) 68:31-34Cardiovascular events in diabetes

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Heart Metab. (2015) 68:31-34 salutini and others

Cardiovascular events in diabetes

cemic control on CV risk is a matter of debate. While an association was reported in epidemiological stud-ies,5 intervention to ensure strict glycemic control has lead to either no effect or a marginal one.6 Nonethe-less, glycemic control remains key to reduce the risk of microvascular complications. Near normal HbA1c is recommended in patients with a long life expectancy, free of or with mild diabetes complications, as was the case of our patient who had nonproliferative reti-nopathy and no other microvascular complications. Yet, Miss AR had signs and symptoms of ischemic heart disease in spite of a minor involvement of coro-nary arteries. This situation may be accounted for by microvascular involvement of the myocardial vascu-lar bed, supporting the need for strict glycemic con-trol. However, treatment should avoid hypoglycemia, which may have been a triggering factor for angina episodes in our patient. Hypoglycemia is associated with an increased risk for CV diseases.7-9 Several mechanisms can contribute to hypoglycemia-induced myocardial isch-emia, including QT-interval elongation, hypokalemia,

catecholamine discharge, platelet activation, and in-creased blood viscosity. Though no ECG was record-ed during a hypoglycemic episode, it seems reason-able to associate the chest discomfort reported by our patient with a low blood glucose level. The risk of hypoglycemia is greater with sulfonyl-ureas (especially glibenclamide) than with other oral antidiabetic agents.10 Moreover, sulfonylureas may worsen the outcome of an ischemic insult because of nonselective interaction with vessel potassium (K+) channels and subsequent impairment of postisch-emic preconditioning.11

Miss AR was then kept on metformin, but shifted from glibenclamide to liraglutide, a glucagon-like pep-tide-1 (GLP-1) receptor agonist, without significant hypoglycemic risk, owing to its glucose-dependent effect on insulin secretion and preserved glucagon response to a drop in blood glucose. GLP-1 recep-tor agonists may also exert extraglycemic effects.12 Preclinical studies have shown a reduction in the size of the infarct area upon ischemic insult,13 but there is no evidence that this is the case in diabetic subjects as well. A number of cardiovascular outcome stud-ies employing GLP-1 receptor agonists are currently ongoing. ELIXA (Evaluation of  LIXisenatide  in Acute coronary syndrome), the first of these trials, shows CV safety of lixisenatide in high-CV-risk patients with a recent acute coronary syndrome episode.14

Miss AR was symptomatic and had a positive stress test. Yet no significant coronary stenosis was documented by coronary angiography. This is com-patible with heart microvascular dysfunction, a factor sufficient to precipitate myocardial ischemia15 as well as to impair the outcome of revascularization pro-cedures in the case of CAD. These patients usually benefit from conventional medical therapy. Addition of trimetazidine can help reduce symptoms because of its cardioprotective properties without affecting blood pressure and heart rate. It has been suggested that trimetazidine may exert its antianginal effect by inhib-iting fatty acid oxidation and improving glycolysis and glucose oxidation16 with a neutral or even favorable effect on glucose metabolism.17,18

Conclusion

Miss AR’s case should encourage consideration of a “cardiologic” approach in selecting antidiabetic treat-ment, in order to avoid conditions (eg, hypoglycemia)

Stress

Rest

Rest

Rest

Stress

Stress

Fig. 2 99mTc stress and rest myocardial scintigraphy. The test showed mild reversible perfusion defects in the apical anteroseptal wall of the left ventricle with apical and inferoapical extension. The perfusion defects normalize at rest.

that may precipitate CV events, and a “metabolic” approach in selecting CV therapy. Such treatment should have a neutral or even favorable effect on glu-cose metabolism in diabetic patients with ischemic heart disease. L

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