_09_CJ_2015_5_Szepietowska

ORIGINAL ARTICLE

Insulin resistance predicts the risk for recurrent coronary events in post-infarction patients

Barbara Szepietowska, Scott McNitt, Valentina Kutyifa, Dan Ryan, James Corsetti, Charles Sparks, Arthur J. Moss, Wojciech Zareba

1Heart Research Follow up Program, University of Rochester Medical Center, Rochester, United States

2Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, United States

Address for correspondence: Prof. Wojciech Zareba, Heart Research Follow-up Program, Cardiology Division, University of Rochester Medical Center; 265 Crittenden Blvd., PO Box 653, Rochester, NY 14642, USA, tel: 585-275-5391, fax: 585-273-5283; e-mail: wojciech.zareba@heart.rochester.edu

Received: 06.01.2015

Accepted: 04.02.2015

Abstract

Background: We investigated the risk for recurrent coronary events associated with insulin resistance in post-infarction patients from the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) study.

Methods: The association between insulin resistance expressed by Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR) and the risk for recurrent coronary events was investigated in a cohort of 1,032 patients evaluated 2 months after myocardial infarction (MI) with a follow-up of 26 months. The endpoint for the study was recurrent coronary event defined as cardiac death, nonfatal MI, or unstable angina, whichever occurred first. We used time dependent survival analysis and Cox proportional hazards regression method to determine the association between HOMA2 categorized as high > 75th percentile and endpoints after adjustment for relevant clinical covariates and series of thrombogenic and dyslipogenic factors.

Results: High HOMA2-IR defined as in fourth quartile (≥ 2.4) was associated with increased risk for recurrent coronary events (HR 1.44; CI 1.03–2.01; p = 0.03) after adjustment for the clinical covariates: age, gender, diabetes, prior MI, pulmonary congestion, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. The highest risk of cardiac events was observed in non-obese patients (body mass index [BMI] ≤ 30 kg/m2) with high HOMA2-IR (HR 1.5; CI 1.02–2.22; p = 0.038). The plasma level of plasminogen activator inhibitor-1 was associated with higher risk for recurrent coronary events in patients with insulin resistance (HR 1.79; CI 1.05–3.03; p = 0.03, interaction p = 0.018).

Conclusions: In conclusion, insulin resistance predicts recurrence of coronary events in post-infarction population. HOMA2-IR is better than BMI in stratifying risk of recurrent coronary events. (Cardiol J 2015; 22, 5: 519–526)

Key words: insulin resistance, myocardial infarction, recurrent coronary events

Introduction

Insulin resistance (IR) plays a role in pathogenesis of metabolic syndrome and diabetes mellitus [1]. For evaluation of IR in larger clinical studies, the Homeostatic Model Assessment (HOMA) index is commonly used [2]. Previously, IR measured in patients with coronary artery disease was associated with increased risk for coronary events and predicted mortality independently from diabetes mellitus [3, 4]. IR increased in-hospital mortality after acute coronary event [5, 6]. The aim of the current study was to evaluate whether HOMA adds predictive value in the population after myocardial infarction (MI) in long-term follow-up and in a large study group. Identifying patients with IR with relation to their body mass index (BMI) may allow better risk stratification and initiation of aggressive risk factor modification after MI when lifestyle changes are more likely to be implemented [7].

Methods

Study population

This investigation is a sub-study of the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) study. Detailed protocol and inclusion criteria have been previously described [8]. THROMBO was a multicenter study examining the effect of lipids and thrombogenic factors on recurrent coronary events, nonfatal MI or cardiac death during a 26-month follow-up in patients with index MI. Between October 1 1994 and June 30 1997 1,045 patients were enrolled and signed the consent for participation in a 2-month post-infarction (baseline) visit. Glucose and insulin measurements were available for 1,032 of 1,045 patients (98.7%) and constituted the study population of this report.

Laboratory measurements

Fasting blood samples were drawn 2 months after index MI. Insulin was measured by radioimmunoassay (coat-A-count diagnostic products). Plasma glucose was measured immediately after the blood was drawn by the enzymatic method using a glucose analyzer. HOMA2-IR was calculated using the online calculator downloaded from http://www.dtu.ox.ac.uk. The BMI was calculated as body weight/height2 and expressed in kilograms per square meter [kg/m2]. The hemostatic factor analyses included measurement of factor VII, factor VIIa, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1 (PAI-1). Additionally, concentrations of apolipoprotein-B (apo-B), apolipoprotein A1, lipoprotein (A), cholesterol, high density lipoprotein and low density lipoprotein cholesterol, triglycerides and C-reactive protein (CRP) were measured.

The endpoint

The endpoint was defined as death due to coronary heart disease, recurrent nonfatal MI or unstable angina episode, whichever occurred first. Unstable angina definition included hospitalization during follow-up with an increase in either frequen-cy or duration of angina symptoms, or development of new angina at rest — whichever occurred first with both requiring ischemic electrocardiogram (ECG) changes without enzyme elevation. A 2-member committee reviewed information on the endpoint events from appropriate medical records.

Statistical analysis

The effects of the HOMA2-IR by quartile on time to endpoint were examined graphically by the Kaplan-Meier method, and the log-rank statistic was used when comparing the difference in survival between each pair of curves. Nineteen patients who died of causes other than coronary heart disease were censored at the time of their death. The multivariate Cox proportional hazards regression analysis was performed with the Cox proportional regression hazards model (SAS PHREG computer program). The regression model was adjusted for factors that play a role in recurrent coronary events. To identify important clinical factors we included in the model previously pre-selected factors (age, sex, race, prior MI, prior stroke, history of diabetes mellitus, index infarct type by ECG [Q-wave vs. non–Q-wave], thrombolytic therapy, pulmonary congestion by chest roentgenogram, and ejection fraction during the index coronary event, and smoking status at enrollment) [8], and additionally we included factor identified by Grace study (hypertension, coronary artery bypass grafting [CABG] and percutaneous transluminal coronary angioplasty [PTCA]) [9]. A significance level of p = 0.05 was used for entering a variable into the basic clinical model. The following parameters enter clinical model: age, male, sex, diabetes mellitus, prior MI, pulmonary congestion on chest roentgenogram, PTCA and CABG. All probability values were 2-tailed, and p < 0.05 was considered significant.

Results

A total of 1,032 patients were analyzed. The clinical characteristics of the entire study population and patients by HOMA2-IR status are presented in Table 1. Patients with high HOMA2-IR were more likely to be younger and less likely to be white, male, obese, male and with history of hypertension and diabetes. They were often treated with diuretics and angiotensin converting enzyme inhibitors. Patients categorized as having higher HOMA2-IR had higher BMI, fibrinogen, PAI-1, von Willebrand factor, apo-B, triglyceride and CRP.

Table 1. Baseline characteristics according to Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR).

Characteristics

All patients

HOMA2 Q1-3

HOMA2 Q4

N

1,032

774

258

Age:

Mean

59 ± 12

59 ± 12

57 ± 12*

60 years

496 (48%)

383 (44%)

113 (49%)*

Male

774 (75%)

598 (77%)

181 (70%)*

White

770 (75%)

594 (77%)

176 (68%)*

BMI [kg/m2]:

Mean

28 ± 5.2

27 ± 4.7

30 ± 5.9**

BMI 30

285 (27%)

177 (23%)

108 (41%)*

History:

Prior myocardial infarction

192 (19%)

140 (18%)

52 (20%)

Hypertension

453 (44%)

319 (41%)

134 (52%)*

Diabetes mellitus

195 (19%)

90 (12%)

105 (41%)*

Stroke

29 (3%)

17 (2%)

12 (5%)

PTCA

122 (12%)

92 (12%)

30 (12%)

CABG

87 (8.5%)

59 (11%)

28 (8%)

Current cigarette smoker

246 (24%)

172 (22%)

74 (29%)

Type of infarction new Q wave

535 (52%)

390 (50%)

145 (56%)

Pulmonary congestion

181 (19%)

121 (16%)

60 (23%)*

Ejection fraction:

Mean

47 ± 12

47 ± 12

47 ± 12

< 0.30

113 (11%)

79 (10%)

34 (13%)

Thrombolytic therapy

355 (34%)

269 (35%)

86 (33%)

Medication at enrolment:

Acetylsalicylic acid

842 (82%)

630 (81%)

212 (82%)

ACE inhibitors

384 (37%)

272 (35%)

112 (43%)*

Beta-blockers

783 (76%)

586 (76%)

197 (76%)

Calcium channel blockers

210 (20%)

157 (20%)

53 (21%)

Diuretics

172 (17%)

110 (14%)

62 (24%)*

Statins

342 (33%)

262 (34%)

83 (32%)

Hemostatic factors:

D-Dimer [ng/mL]

521 ± 638

527 ± 697

509 ± 422

Factor VII [%]

103 ± 43

103 ± 42

103 ± 45

Factor VIIa [ng/mL]

2.5 ± 1.7

2.5 ± 1.6

2.6 ± 1.8

Fibrinogen [mg/dL]

352 ± 88

346 ± 82

370 ± 101*

Plasminogen activator inhibitor-1 [ng/mL]

28 ± 27

24 ± 22

39 ± 38**

Von Willebrand factor [U/dL]

149 ± 68

142 ± 64

168 ± 76**

Lipid and metabolic factors:

118 ± 25

Apolipoprotein A1 [mg/mL]

118 ± 25

121 ± 27

118 ± 24

Apolipoprotein B [mg/mL]

123 ± 28

195 ± 43

126 ± 29*

Cholesterol [mg/mL]

197 ± 44

201 ± 43*

HDL-cholesterol [mg/mL]

39 ± 11

39 ± 11

37 ± 11*

LDL-cholesterol [mg/mL]

120 ± 38

120 ± 37

119 ± 39

Lipoprotein(a) [mg/mL]

24 ± 23

25 ± 23

22 ± 21

Triglyceride [mg/mL]

200 ± 117

187 ± 102

239 ± 145**

C-reactive protein [mg/L]

0.49 ± 0.7

0.42 ± 0.6*

0.7 ± 1.0*

Values are given as total number of patients and percentage or mean ± standard deviation; *p < 0.05 and **p < 0.0001 difference between patients with HOMA2-IR Q4 vs. Q1-3; ACE-inhibitors — angiotensin converting enzyme inhibitors; BMI — body mass index; CABG — coronary artery bypass graft surgery; PTCA — percutaneous transluminal coronary angioplasty

The risk of recurrent cardiac events in patients with high HOMA2-IR

During a mean follow-up of 1.7 ± 0.89 years, the combined primary endpoint was met in 199 su­-bjects including: 127 patients with unstable angina, 52 patients with MI and 20 patients with cardiac death.

In Kaplan-Meier survival analysis, patients with highest HOMA2-IR quartile had a significantly higher probability of recurrent coronary events (log-rank, p = 0.025) (Fig. 1).

70948.png

Figure 1. Cumulative probability of recurrent cardiac events in post-infarction patients by HOMA2-IR quartiles.

In the multivariate models after adjustment for age, gender, diabetes, prior MI, pulmonary congestion on chest roentgenogram, PTCA and CABG patients with Q4: HOMA2-IR were at higher risk for recurrent coronary events (hazard ratio [HR] 1.44; confidence interval [CI] 1.03–2.01; p = 0.03) compared to patients in the lower 3 quartiles (Table 2). When HOMA2-IR was analyzed separately for cardiac death, MI and unstable angina, only unstable angina was predicted with statistical significance (Table 2).

Table 2. The contribution of Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR) (Q4:Q1-3) to the risk of experiencing a recurrent cardiac event for patients in the top quartile (Q4 2.4) compared to patients in the lower 3 quartiles.

Number of patients; events

Hazard ratio

95% confidence interval

P

Recurrent coronary event (cardiac death or myocardial infarction or unstable angina)

933; 76

1.44

1.03–2.01

0.030

Unstable angina

933; 123

1.51

1.02–2.25

0.039

Myocardial infarction

933; 48

1.19

0.63–2.26

0.579

Cardiac death

933; 23

1.34

0.55–3.27

0.508

The survival model includes adjustment for the following clinical variables: age, male sex, diabetes mellitus, prior myocardial infarction, pulmonary congestion on chest roentgenogram, percutaneous coronary intervention and coronary artery bypass grafting

To examine whether the association between HOMA2-IR and clinical outcome was driven by a concurrent diagnosis of diabetes, we additionally analyzed interaction between diabetes status and HOMA2-IR that was not statistically different (interaction p = 0.07).

Clinical outcome of different metabolic groups as function of BMI and IR

We assessed whether BMI status affects relationship between insulin sensitivity and risk for recurrent cardiac events. Kaplan-Meier survival analysis showed that non-obese patients with high HOMA2-IR had a significantly higher probability of recurrent coronary events (log-rank, p = 0.024). Non-obese and obese with low HOMA had a similarly low risk (Fig. 2).

70897.png

Figure 2. Cumulative probability of recurrent cardiac events in post-infarction patients with respect to body mass index and HOMA2-IR status. Gray line: non-obese with HOMA2-IR Q4, light blue: obese with HOMA2-IR Q4, blue: obese with HOMA2-IR Q3-Q1 and black: non-obese with HOMA2-IR Q3–Q1.

In the multivariate models after adjustment for relevant clinical covariates, non-obese insulin resistance patients remained at highest risk for recurrent coronary event (HR 1.50; CI 1.02–2.22; p = 0.038) (Table 3).

Table 3. The contribution of Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR) (Q4:Q1-3) and obesity to the risk of experiencing a recurrent cardiac event. Reference group: non-obese with HOMA2-IR Q3-Q1, total: n = 933, number of events: 176.

Number of patients; events

Hazard ratio

95% confidence interval

P

Reference group: non-obese and obese with HOMA2-IR Q3-Q1

699; 118

Non-obese with HOMA2-IR Q4

136; 35

1.50

1.02–2.22

0.038

Obese with HOMA2-IR Q4

98; 23

1.34

0.84–2.16

0.214

The survival model includes adjustment for the following clinical variables: age, male, diabetes mellitus, prior myocardial infarction, pulmonary congestion on chest roentgenogram, percutaneous coronary intervention and coronary artery bypass grafting

The contribution of thrombogenic and dyslipogenic factors for risk for recurrent coronary events

We evaluated if concomitant presence of highest risk quartile for evaluated thrombogenic and dyslipogenic factors and high HOMA2-IR will additionally incensed risk for recurrent coronary events. PAI-1 was associated with higher risk in patients with IR (HR 1.79; CI 1.05–3.03; p = 0.03, interaction p = 0.018) (Table 4).

Table 4. The contribution of Homeostatic Model Assessment 2 for Insulin Resistance (HOMA2-IR) (Q4:Q1-3) and thrombogenic and dyslipogenic factors (Q4:Q1-3) to cardiac events.

HOMA2-IR Q4

HOMA2-IR Q1-3

Interaction P

Hazard ratio (95% CI)

P

Hazard ratio (95% CI)

P

Plasminogen activator inhibitor-1 Q4

1.79 (1.05–3.03)

0.030

0.74 (0.46–1.26)

0.23

0.018

Apolipoprotein A1 Q1

2.5 (1.4–4.45)

0.001

1.23 (0.78–1.94)

0.37

0.055

Apolipoprotein B Q4

1.70 (0.94–3.11)

0.066

1.74 (1.18–2.57)

0.004

0.943

C-reactive protein Q4

1.76 (1.00–3.11)

0.050

1.33 (0.05–2.07)

0.2

0.435

HDL-cholesterol Q1

0.92 (0.51–1.66)

0.79

0.99(0.63–1.58)

0.99

0.843

LDL-cholesterol Q4

1.37 (0.75–2.5)

0.29

1.27 (0.85–1.92)

0.23

0.843

Triglycerides Q4

0.89 (0.51–0.54)

0.69

0.8 (0.5–1.28)

0.35

0.761

Factor VIIa Q4

1.54 (0.87–2.75)

0.137

0.85 (0.55–1.34)

0.50

0.1139

Von Willebrand factor Q4

1.24 (0.72–2.14)

0.423

0.96 (0.63–1.48)

0.88

0.466

Fibrinogen Q4

1.1 (0.73–1.67)

0.375

1.07 (0.62–1.85)

0.78

0.929

The survival model includes adjustment for the following clinical variables: age, male, diabetes mellitus, prior myocardial infarction, pulmonary congestion on chest roentgenogram, percutaneous coronary intervention and coronary artery bypass grafting

Discussion

In primary risk stratification, IR predicts development of cardiovascular disease independently of diabetes mellitus [10–12]. In acute hospital setting, IR is associated with increased mortality after acute coronary event [5, 6]. In our multicenter prospective study, IR predicts recurrence of coronary events in post-infarction population. Analysis of specific components suggested that the main effect was related to prediction of unstable angina. Our study is consistent with previous observations, furthermore emphases significance of IR in development of acute cardiac events in population at high cardiovascular risk. Importantly, IR was associated with adverse prognosis after adjustment for important clinical factors including diabetes mellitus.

IR was measured 2 months after MI and therefore it is less likely to be associated with adrenergic surge as a part of the acute stress responses, but rather a representation of metabolic disturbances. It has been postulated that IR in the post-myocardial period may predispose patients to micro vascular, myocardial injury and larger infract size [13]. Emerging evidence supports direct pro atherogenic effect of IR [14, 15], as well as its direct adverse effect on myocardial contractility [16].

An adipocentric view of the metabolic disturbances considers obesity the major clinical component for IR in peripheral metabolic tissues. However, the link between obesity and IR is complex, as indicated by the fact that some extremely obese people are glucose tolerant, while others with a mild degree of obesity develop severe IR and diabetes. In our study, patients identified as non-obese with IR had a higher risk for recurrent coronary events. Although obesity is an independent predictor of clinical coronary disease in the Framingham study [17], the association becomes weaker after adjustment for hypertension, hypercholesterolemia: features classically associated with obesity [18]. Noteworthy among people with established coronary artery disease is the fact that BMI is inversely associated with mortality, phenomenon known as “obesity paradox” in review [19]. It has been previously suggested that perhaps BMI is not a good parameter to explain the complex association of obesity and cardiovascular disease. Other parameters like visceral adiposity, body composition, waist circumference, body fat and free fat mass have a role in clinical practice [20]. Our study showed that HOMA2-IR is a better prognostic factor than BMI in predicting risk for recurrent coronary events suggesting that intracellular lipid accumulation in ectopic tissue triggers pathological responses with subsequent impairment in insulin signaling in review [21].

In our population, patients with higher HOMA2-IR index had higher level of von Willebrand factor, a marker of endothelial injury previously shown to be an independent risk factor for recurrent cardiac events in patients with diabetes [22]. Patients with higher HOMA2-IR had, similarly to patients with metabolic syndrome, higher level of apo-B, PAI-1 and triglyceride, but presence of metabolic syndrome in our population did not predict risk for recurrent coronary events [23]. In our study, patients with high HOMA2-IR and PAI-1 had increased risk for recurrent coronary events, but not patients with lower HOMA2-IR and high PAI-1 suggesting that presence of IR will modify risk associated with high PAI-1. The link between hypofibrinolysis and IR has been previously postulated [24, 25], but significance of PAI-1 is not limited to thrombolysis [26]. Elevated plasma level of PAI-1 has been shown to predict risk for recurrent coronary events and first MI [27, 28], but its predictivity is attenuated after adjustment for IR [29].

Currently there are no guidelines for the treatment of IR, especially in patients with cardiovascular risk [30]. It has been recognized that increased physical activity will improve insulin sensitivity [31]. For pharmacological intervention, metformin and insulin sensitizers for type 2 diabetes treatment [32] or antihypertensive and lipid lowering drugs can also improve insulin sensitivity [33].

Conclusions

Our findings indicate that IR is a good clinical marker of increased risk and improving insulin sensitivity may modify cardiovascular risk. HOMA2-IR is better than BMI in stratifying the risk of recurrent coronary events. Multilevel intervention to increase insulin sensitivity in people after MI may influence the clinical outcome.

Acknowledgements

This study was supported by research grant HL-48259 and HL-30616 from the National Institute of Health, Bethesda, MD. We would like to thank Patricia Severski from Heart Research Follow up Program for her assistance in data management and data analysis for THROMBO study and for this manuscript.

Conflict of interest: None declared

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