Insulin resistance (IR) is typically defined as decreased sensitivity and responsiveness to metabolic actions of insulin that promote glucose disposal. The important feature of diabetes, obesity, glucose intolerance, and dyslipidemia, is also a prominent component of cardiovascular disorders including coronary artery disease (CAD), atherosclerosis and hypertension.1-4 Several studies have shown that IR is a significant risk factor for CAD and cardiovascular events in patients with or without type 2 diabetes mellitus (T2DM).5,6 Compared with non-diabetic counterparts, patients with T2DM often have IR and require more cardiovascular care. Unfortunately, patients with T2DM continue to have significant complications after percutaneous coronary intervention (PCI), including restenosis, myocardial infarction and early or late mortality.7
Homeostasis model assessment (HOMA) index is used to assess IR in many patients, in whom fasting serum insulin and glucose levels are simply measured.8,9 It is not only a perfect parameter for investigating the role of IR and insulin secretion in the development of diabetes, but also a good expression for evaluating the jeopardy of IR in Chinese with cardiovascular diseases.10 Considering that IR is a risk factor for CAD and correlated with the outcome of CAD patients, we examined the prognostic value of IR in patients undergoing sirolimus-eluting stent (SES)-based PCI using the HOMA index.
We studied 467 consecutive patients undergoing PCI with SES implantation from July 2007 to May 2008 in the Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The patients who met the following criteria were excluded: (1) acute coronary syndrome and primary angioplasty; (2) history of PCI or coronary artery bypass graft; (3) NYHA class III or IV before PCI despite optimal pharmacological therapy; (4) inflammation-related diseases; (5) severe liver and kidney dysfunction; and (6) malignant tumor.
The protocol of this study was approved by the Hospital Ethics Committee, and written informed consent was obtained from all patients.
Pre-medications with aspirin 100 mg and clopidogrel 75 mg daily were commenced at least 2-3 days before the procedure. Loading doses of aspirin (300 mg) and clopidogrel (450-600 mg) were always given to those who were not pre-medicated. Coronary angiography and PCI procedures were performed using standard techniques through femoral or radial approaches.11 Angiographic analysis was carried out by 2 experienced interventional cardiologists, who were not informed the study protocol. The number of diseased coronary arteries (luminal diameter narrowing ≥70%) was recorded, and patients with stenosis of the left main coronary artery ≥50% were considered to have two-vessel disease.12 All patients enrolled in this study underwent a successful angioplasty and a SES implantation, and complete revascularization was achieved if there was no remnant vessel stenosis ≥30%.
After the procedure, the patients were maintained with clopidogrel 75 mg daily for at least 1 year, and aspirin 100 mg daily infinitely. Other medications such as statins, angiotensin-converting enzyme inhibitors, beta-blockers and calcium antagonists were administered when indicated.
Blood samples were collected after overnight fasting, and stored at -70°C prior to analysis. Serum glucose level was measured by the glucose oxidase method and insulin concentration was assessed using radioimmunoassay techniques. The insulin resistance index (IRI) was expressed by homeostasis model assessment for insulin resistance (HOMA-IR) calculated from (fasting serum glucose (mmol/L)×fasting plasma insulin (mU/L))/22.5.8 IRI ≥2.69 was defined as IR and IRI <2.69 was insulin sensitivity based on a scale Chinese population study.12 Serum high-sensitivity C-reactive protein (hsCRP) level was determined using a high-sensitivity ELISA kit (Biocheck Laboratories, USA). Serum lipid profiles including triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and lipoprotein(a), and blood urea nitrogen and creatinine were assessed using standard methods.13
The 467 patients were followed up in a special outpatient clinic or by telephone conversation every 3 months after discharge. Cardiac events including cardiac death, non-fatal myocardial infarction and recurrent angina pectoris were recorded. Myocardial infarction was defined as presence of typical chest pain, electrocardiographic ST-segment elevation with or without Q waves, and serum cardiac enzyme elevations at least twice the upper limit of normal range. Cardiac death was considered if death occurred suddenly or was associated with documented myocardial infarction, congestive heart failure and malignant ventricular arrhythmias. Recurrent angina pectoris was defined by the Canadian Cardiovascular Society (CCS) class ≥II grade. In order to guarantee rigorous data quality, all cardiac events were reviewed by two experienced interventional cardiologists.
All statistical analyses were performed using SPSS 13.0 for Windows (SPSS Inc, Chicago, IL, USA). Baseline characteristics were compared using the chi-square test for categorical variables (presented as counts and percentages) and independent-sample t test for continuous variables (mean ± standard deviation (SD)). Abnormally distributed data were analyzed using the Mann-Whitney U test. The unadjusted cumulative incidence of cardiac events was determined by the Kaplan-Meier method and the log-rank test. After testing all variables, those associated with event rates on univariate analysis at P ≤0.2 entered a multivariate Cox proportional hazards regression model with a backward stepping algorithm to analyze the independent risk factors for cardiac events during follow-up. All tests of significance were two-tailed and a P value <0.05 was considered statistically significant.
Of the 467 patients, 104 had an IRI ≥2.69 (the IR group), and 363 had an IRI <2.69 (the non-IR group). T2DM, hypertension, and multi-vessel disease were more common in the IR group, and the levels of serum glucose at fasting and 2 hours after glucose load, insulin, hemoglobin A1c (HbA1c), triglycerides, lipoprotein-a as well as body mass index and stent length were higher, but the level of HDL-C was lower (Table 1). And IR was significantly associated with hypertension, diabetes, dyslipidemia, obesity, and multi-vessel disease by univariate analysis (Table 2).
In 122 patients with T2DM, 44 (36.1%) had IR. The levels of fasting glucose ((8.07±3.14) vs. (6.80±2.28) mmol/L), insulin ((18.16±15.72) vs. (6.56±2.30) mU/L), and triglycerides ((2.17±1.85) vs. (1.69±0.79) mmol/L) were higher and left ventricular ejection fraction ((60.24±9.96)% vs. (63.93±5.61)%) was lower in patients with T2DM and IR than in those with non-RI (all P <0.05); but body mass index, stent length, HbA1c, incidence of hypertension and multi-vessel disease were not significantly different.
Of 345 non-diabetic patients, 60 (17.4%) experienced IR. The levels of fasting glucose ((5.83±1.18) vs. (5.10±0.89) mmol/L), glucose 2 hours after load ((9.22±3.50) vs. (7.55±2.56) mmol/L), fasting insulin ((17.37±7.07) vs. (6.01±2.57) mU/L), triglycerides ((2.49±2.40) vs. (1.77±1.02) mmol/L), as well as body mass index ((26.68±3.31) vs. (24.33±2.80) kg/m2) were higher and multi-vessel disease (63.3% vs. 50.8%) was more common in non-diabetic patients with or without RI (all P <0.05).
During the follow-up ((9.03±3.07) months for the IR group; (9.14±2.61) months for the non-IR group), 6 patients (1.28%) had cardiac death, 2 (0.43%) suffered from non-fatal myocardial infarction, and 22 (4.71%) had recurrent angina pectoris. There was a significant difference in cardiac events between the two groups (Figure 1A).
In the T2DM subgroup, 4 patients (3.28%) had cardiac death and 10 (8.20%) experienced recurrent angina pectoris, but none had non-fatal myocardial infarction. There were a non significantly higher rate of cardiac death and a significantly higher incidence of recurrent angina pectoris in the RI group than in the non-RI group (Figure 1B). In the non-diabetic patients, 2 had cardiac death (0.58%), 2 (0.58%) suffered from non-fatal myocardial infarction, and 12 (3.48%) had recurrent angina pectoris. No significant differences were found between the two groups (Figure 1C).
The Kaplan-Meier analysis with the log-rank test revealed that patients in the IR group had higher cumulative rates of MACE (P=0.002), cardiac death (P=0.009) and recurrent angina pectoris (P=0.049) than those in the non-IR group during the follow-up (Figure 2). In the T2DM subgroup, the presence of IR was not associated with a significant increase in cardiac death (log-rank test, P=0.098), but correlated with an increased incidence of recurrent angina pectoris (log-rank test, P=0.030) (Figure 3A and 3B). In addition, IR was significantly associated with reduced MACE-free survival (log-rank test, P=0.027), but not with recurrent angina pectoris (log-rank test, P=0.919) in the non-diabetic patients (Figure 3C and 3D).
Cox regression analysis
Cox proportional hazard regression analysis was made to adjust baseline covariates, including age, gender, T2DM, hypertension, smoking history, presentation of acute coronary syndrome, dyslipidemia, obesity, left ventricular ejection fraction and multi-vessel disease. IR was an independent risk factor for the incidence of MACE in all patients (OR=2.76, 95% CI=1.35-5.47, P=0.034). The significant predictors for recurrent angina pectoris included age (OR =3.25, 95% CI=1.15-9.72, P=0.047), T2DM (OR =3.74, 95% CI=1.23-8.46, P=0.020), and multi-vessel disease (OR=5.33, 95% CI=1.09-11.19, P=0.025).
In the T2DM subgroup, hypertension (OR=2.87, 95% CI=1.54-7.84, P=0.043) and hypercholesterolemia (OR=2.91, 95% CI=1.24-8.98, P=0.033) but not IR (OR=1.69, 95% CI=0.74-3.51, P=0.137) were independent predictors for MACE occurrence during the follow-up. IR (OR =3.35, 95% CI =1.07-13.59, P =0.013) and multi-vessel disease (OR =2.19, 95% CI =1.01-5.14, P=0.044) were significantly associated with recurrent angina pectoris. And IR was not shown to be an independent risk factor for the occurrence of MACE in the non-diabetic patients.
Thus IR was an independent risk factor for the occurrence of MACE in the non-diabetic patients.
This study demonstrated that the presence of IR was associated with a striking increase in mortality, non-fatal myocardial infarction and recurrent angina pectoris during the follow-up. Despite the association of IR with multiple high-risk features known to affect the prognosis of patients after drug-eluting stent-based PCI, at least moderate IR was one of the strongest independent predictors for diminished survival.
IR is a key component of metabolic syndrome, and plays an important role in various cardiovascular disorders.14,15 Numerous studies have demonstrated detrimental impacts of IR on the development of coronary atherosclerosis, plaque instability, and cardiovascular events in patients with or without T2DM.16 Hyperinsulinemia, an indirect indicator for insulin sensitivity, is closely associated with mortality due to cardiovascular diseases.5,17 A recent study on insulin resistance atherosclerosis showed that IR rather than insulin concentration is an independent and powerful risk factor for CAD.18 The mechanism by which IR provokes cardiovascular disease is mainly related to the development of metabolic syndrome. Patients with IR exhibit high concentrations of serum triglyceride, lipoprotein, and apolipoprotein B, as well as a low concentration of HDL-cholesterol,19,20 indicating that dyslipidemia is associated with the development of cardiovascular disease. In addition, IR has been shown to reduce flow-mediated vasodilation of the brachial artery, cause endothelial dysfunction, trigger inflammatory signaling, and increase the formation of advanced glycation end products.21-24 As reported previously,25,26 IR was found to be correlated with triglyceride level and was inversely related to HDL-cholesterol in the present study.
Drug-eluting stents have now been applied to almost all types of coronary lesions in patients with various clinical presentations, leading to improved outcomes in those patients at high-risk.27,28 To date, however, few large-scale studies have been conducted to examine the relationship between IR and long-term clinical outcomes in patients undergoing SES-based PCI. Lazzeri et al29 have observed that IR, as assessed by HOMA index, was quite common and helpful in the early prognostic stratification, and represented an independent predictor of in-hospital mortality in non-diabetic patients with ST-elevation myocardial infarction undergoing primary PCI. Yun et al30 analyzed 98 consecutive non-diabetic patients who underwent elective coronary angioplasty, and revealed that IRI ≥2.6 was an independent predictor of in-hospital and 30-day MACE rates. However, these studies were limited by small sample size, chaos of angioplasty methods, and short period of follow-up. In the present study, we enrolled more patients, and excluded those with acute coronary syndrome, primary PCI, and severe cardiac dysfunction. This would make the assessment of prognostic value of IR for patients undergoing PCI more exactly. The results indicated that IR may significantly influence the MACE-free survival rate of patients undergoing SES-based PCI and is an independent risk factor for cardiac death and non-fatal myocardial infarction during the follow-up.
Recurrent angina pectoris after PCI is one of the important factors that influence the life quality of patients with CAD. The mechanisms may include in-stent restenosis, stent thrombosis, side branch involvement, coronary spasm, multi-vessel disease, and plaque progression.31-33 In patients with IR, coronary spasm may be induced by an imbalance between endothelin-1 and NO secretion, and thrombosis and plaque instability are easily triggered by activating inflammatory signaling, increased platelet function, and anticoagulation/fibrolysis dysfunction.22,34-36 In addition, multi-vessel disease and long lesions which are more common in patients with IR could cause frequent distal occlusion. Nishimura et al37 reported that IR might be involved in the progression of non-culprit coronary atherosclerosis and contribute to the poor prognosis after PCI with bare metal stent implantation in hemodialysis patients. Our study showed that patients with T2DM more frequently experienced recurrent angina pectoris after PCI with SES implantation, especially for those with IR and multi-vessel disease.
As previously reported that hypertension and hypercholesterolemia are significantly associated with MACEs in patients undergoing PCI,38-40 the two factors are also independent predictors for the incidence of MACE during the follow-up in patients with T2DM. It has been shown that hypertension and dyslipidemia are closely associated with IR.41,42
In conclusion, IR is significantly associated with poor long-term outcomes in patients after PCI with SES implantation. Appropriate therapies for ameliorating IR may be crucial to reduce subsequent cardiac events in these patients.
1. Laws A, Reaven GM. Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations. J Intern Med 1992; 231: 25-30.
2. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607.
3. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683-689.
4. Mykkanen L, Zaccaro DJ, Wagenknecht LE, Robbins DC, Gabriel M, Haffner SM. Microalbuminuria is associated with insulin resistance in nondiabetic subjects. Diabetes 1998; 47: 793-800.
5. Yanase M, Takatsu F, Tagawa T, Arai K, Kovasu M, Horibe H, et al. Insulin resistance and fasting hyperinsulinemia are risk factors for new cardiovascular events in patients with prior coronary artery disease and normal glucose tolerance. Circ J 2004; 68: 47-52.
6. Jeppesen J, Hansen TW, Rasmussen S, Ibsen H, Torp-Pedersen C, Madsbad S. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease: a population-based study. J Am Coll Cardiol 2007; 49: 2112-2119.
7. Marso SP, Murphy JW, House JA, Safley DM, Harris WS. Metabolic syndrome-mediated inflammation following elective percutaneous coronary intervention. Diab Vasc Dis Res 2005; 2: 31-36.
8. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.
9. Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio heart study. Diabetes Care 1997; 20: 1087-1092.
10. Li G, Hu Y, Yang W, Jiang Y, Wang J, Xiao J, et al. Effects of insulin resistance and insulin secretion on the efficacy of interventions to retard development of type 2 diabetes mellitus: the Da Qing IGT and Diabetes Study. Diabetes Res Clin Pract 2002; 58: 193-200.
11. Zhang RY, Ni JW, Zhang JS, Hu J, Yang ZK, Zhang Q, et al. Long term clinical outcomes in patients with moderate renal insufficiency undergoing stent based percutaneous coronary intervention. Chin Med J 2006; 119: 1176-1181.
12. Pan XR, Yang WY, Liu J. The prevalence rate of diabetes and its risk factors in China 1994. Chin J Intern Med (Chin) 1997; 6: 384-389.
13. Pu LJ, Lu L, Shen WF, Zhang Q, Zhang RY, Zhang JS, et al. Increased serum glycated albumin level is associated with the presence and severity of coronary artery disease in type 2 diabetic patients. Circ J 2007; 71: 1067-1073.
14. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002; 288: 2709-2716.
15. Karabulut A, Iltumur K, Toprak N, Tuzcu AK, Kara IH, Kaplan A, et al. Insulin response to oral glucose loading and coronary artery disease in nondiabetics. Int Heart J 2005; 46: 761-770.
16. Nakamura Y, Saitoh S, Takagi S, Ohnishi H, Chiba Y, Kato N, et al. Impact of abnormal glucose tolerance, hypertension and other risk factors on coronary artery disease. Circ J 2007; 71: 20-25.
17. 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: 952-957.
18. Rewers M, Zaccaro D, D'Agostino R, Haffner S, Saad MF, Selby JV, et al. Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study. Diabetes Care 2004; 27: 781-787.
19. Young MH, Jeng CY, Sheu WH, Shieh SM, Fuh MM, Chen YD, et al. Insulin resistance, glucose intolerance, hyperinsulinemia and dyslipidemia in patients with angiographically demonstrated coronary artery disease. Am J Cardiol 1993; 72: 458-460.
20. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, et al. Mechanisms of hepatic artery very low density lipoprotein overproduction in insulin resistance: evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem 2000; 275: 8416-8425.
21. Potenza MA, Marasciulo FL, Chieppa DM, Briqiani GS, Formoso G, Quon MJ, et al. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am J Physiol 2005; 289: H813-H822.
22. Basili S, Pacini G, Guagnano MT, Manigrasso MR, Santilli F, Pettinella C, et al. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol 2006; 48: 2531-2538.
23. Wendt T, Harja E, Bucciarelli L, Qu W, Lu Y, Rong LL, et al. RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes. Atherosclerosis 2006; 185: 70-77.
24. Mizuno T, Matsui H, Imamura A, Numaguchi Y, Sakai K, Murohara T, et al. Insulin resistance increases circulating malondialdehyde-modified LDL and impairs endothelial function in healthy young men. Int J Cardiol 2004; 97: 455-461.
25. Laws A, Reaven GM. Evidence for an independent relationship between insulin resistance and fasting plasma HDL-cholesterol, triglyceride and insulin concentrations. J Intern Med 1992; 231: 25-30.
26. Yarnell JW, Sweetnam PM, Marks V, Teale JD, Bolton CH. Insulin in ischemic heart disease: are associations explained by triglyceride concentrations: the Caerpholly prospective study. Br Heart J 1994; 171: 293-296.
27. Urban P, Gershlick AH, Guagliumi G, Guyon P, Lotan C, Schofer J, et al. Safety of coronary sirolimus-eluting stents in daily clinical practice: one year follow-up of the e-Cypher registry. Circulation 2006; 113: 1434-1441.
28. Lopez-Minguez JR, Nogales JM, Morales A, Alonso R, Gonzalez R, Merchan A. Clinical and angiographic follow-up in patients with Cypher or Taxus stents in populations with high percentage of trial excluded lesions. Cardiovasc Revasc Med 2005; 6: 92-98.
29. Lazzeri C, Sori A, Chiostri M, Gensini GF, Valente S. Prognostic role of insulin resistance as assessed by homeostatic model assessment index in the acute phase of myocardial infarction in nondiabetic patients submitted to percutaneous coronary intervention. Eur J Anaesthesiol 2009; 1: 1-7.
30. Yun KH, Jeong MH, Kim KH, Hong YJ, Park HW, Kim JH, et al. The effect of insulin resistance on prognosis of non-diabetic patients who underwent percutaneous coronary intervention. J Korean Med Sci 2006; 21: 212-216.
31. Zhao FH, Chen YD, Song XT, Pan WQ, Jin ZN, Yuan F, et al. Predictive factors of recurrent angina after acute coronary syndrome: the global registry acute coronary events from China (Sino-GRACE). Chin Med J 2008; 121: 12-16.
32. Feuvre CL, Montalescot G, Rosey G, Collet JP, Beygui F, Choussat R, et al. Predictive factors of cardiac events after implantation of sirolimus-eluting stents for treatment of in-stent restenosis. Int J Cardiol 2006; 109: 207-212.
33. Paudel B, Xuan G, Chun Z. Analysis of clinical factors affecting the restenosis following percutaneous coronary intervention. Nepal Med Coll J 2005; 7: 101-106.
34. Gianetti J, Parri MS, Sbrana S, Paoli F, Maffei S, Paradossi U, et al. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: a 6 months prospective study. Thromb Res 2006; 118: 487-493.
35. Jacopo G, Elisabetta V, Silverio S, Massimiliano M, Sergio B, Grazia AM, et al. Identification of platelet hyper-reactivity measured with a portable device immediately after percutaneous coronary intervention predicts in stent thrombosis. Thromb Res 2007; 121: 407-412.
36. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 13: 1888-1904.
37. Nishimura M, Tokoro T, Nishida M, Hashimoto T, Kobayashi H, Yamazaki S, et al. Association of insulin resistance with de novo
coronary stenosis after percutaneous coronary artery intervention in hemodialysis patients. Nephron Clin Pract 2008; 109: 9-17.
38. Gruberg L, Weissman NJ, Waksman R, Fuchs S, Deible R, Pinnow EE, et al. The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: The obesity paradox? J Am Coll Cardiol 2002; 39: 578-584.
39. Park MW, Par JH, Yoon SK, Baek JY, Koh YS, Shin DI, et al. Progression of untreated nonculprit coronary lesions: long-term clinically-driven PCI rate and associated independent predictors. Circulation 2008; 118: S747-S748.
40. Chan AW, Bhatt DL, Chew DP, Quinn MJ, Moliterno DJ, Topol EJ, et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation 2002; 105: 691-696.
41. Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 2001; 104: 342-345.
42. de Jongh RT, Serné EH, IJzerman RG, de Vries G, Stehouwer CD. Impaired microvascular function in obesity implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 2004; 109: 2529-2535.