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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Eduardo Alegria-Ezquerra
Triglyceride (TG) to high-density lipoprotein (HDL) ratio values >2.75 in men and >1.65 in women were found in the Metabolic Syndrome in Active Subjects (MESYAS) study -18,778 active workers enrolled in 3 insurance companies in Spain- to be highly predictive of the metabolic syndrome (MS) diagnosis. TG/HDL ratio was also found to have a high predictive value of a first coronary event regardless of body mass index (BMI).
Metabolic syndrome (MS) is a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus (DM2) which occur together more often than by chance alone. These risk factors include: a) raised blood pressure; b) a distinct dyslipidemic phenotype (raised triglycerides and lowered high-density lipoprotein cholesterol); c) altered glucose metabolism; d) central obesity. The different diagnostic criteria been proposed by different organizations over the past decade are summarized in table 11,2. Table 1. The four main definitions of metabolic syndrome
1 > 90 cm (M) or > 85 cm (F) 2 Body mass index > 30 kg/m2 3 > 94 cm (M) or > 80 cm (F) 4 > 40 inches (M) or > 35 inches (F) 5 Impaired fasting glucose, glucose intolerance, type 2 diabetes or any other evidence 6 Plasma insulin > 75th percentile 7 Plasma triglyceride > 150 mg/dl 8 High density lipoprotein < 35 mg/dl (M) or < 39 mg/dl (F) 9 Plasma triglyceride > 177 mg/dl 10 High density lipoprotein < 39 mg/dl 11 High density lipoprotein < 40 mg/dl (M) or < 50 mg/dl (F) 12 Urinary albumin excretion > 20 mcg/min or albumin-to-creatinin ratio > 30 mg/g The MS is clinically important for several reasons: a) it allows to identify patients with a high risk of developing atherothrombotic complications, DM2, or both; b) it expands our knowledge on the mechanisms linking their components and the development of atherosclerosis; c) it has prompted epidemiological and clinical investigation on preventive approaches based on lifestyle and drug therapy
Insulin is produced by the pancreas in response to hyperglycemia and stimulates glucose use differently in various tissues (table 2)1. Table 2. A summary of the effects of insulin in different tissues
Insulin resistance (IR) occurs when there is a decrease in the responsiveness of adipose, muscle and liver cells to the action of insulin. As a consequence, circulating insulin and glucose levels remain high, which leads to several pathologic changes. Insulin resistance is linked to several known cardiovascular risk factors (dyslipidemia, hypertension, DM2, obesity) and is a hallmark of many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models has gained more and more importance for epidemiological studies and clinical and basic science investigations, but its use in clinical practice has been scarce.
Direct and indirect methods are currently employed to assess insulin resistance. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic-euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions, rather difficult to achieve and control; they may be useful for intensive physiological studies on small numbers of subjects. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Some surrogate indexes are well-established methods to indirectly assess insulin sensitivity/resistance (e.g., QUICKI, HOMA), that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic); these indexes could be more appropriate for large epidemiological studies. The determination of fasting intact proinsulin or the proinsulin/insulin ratio are currently used mostly to analyze the effects of new drugs on the insulin secreting cells3,4.
Some surrogate indexes have attempted to help in the recognition of insulin resistance in patients with overweight or glucose abnormalities. In the clinical scenario, the presence or absence of insulin resistance adds nothing to the preventive measures required for a patient with metabolic syndrome; consequently, there are no indications for assessing insulin sensitivity by any of the available methods. The Spanish MESYAS (Metabolic Syndrome in Active Subjects) group has studied the correlation between TG/HDL ratio and the presence of MS in 18,778 active workers (77.6% men; mean age 42.2 ± 10.7 years) enrolled in 3 insurance companies in Spain from their annual health examinations. Prevalences of MS were 18.8% in men and 6.1% in women. Mean value of the TG/HDL ratio was 2.50 ± 2.2 and increased in parallel to the number of MS components present. Subjects with MS had a ratio that was 2 times higher compared with those without (5.10 vs 2.03, p <0.001). Receiver operating characteristic curves showed that values >2.75 in men and >1.65 in women of the TG/HDL ratio were highly predictive to the diagnosis of MS with 80% sensitivity and 78% specificity5. Another more recent study of this group has aimed to correlate the TG/HDL ratio with the incidence of a first coronary event (myocardial infarction, unstable angina or subclinical myocardial ischemia detected through electrocardiogram abnormalities) in male workers according to body mass index (BMI) in a case-control study design (208 cases and 2080 controls, mean age 49.9 years). TG/HDL ratio was significantly higher in cases compared to controls, and a significant increasing prevalence of cases and mean TG/HDL in each category of BMI was present (figure 1). Multivariable analysis demonstrated that TG/HDL increased by 50% the risk of a first coronary event (OR: 1.47; 95% CI 1.26-1.71), meanwhile LDL-C values obtained more moderate increased-risk (OR: 1.01; 95% CI 1.005-1.012); metabolic syndrome (OR: 1.76; 95% CI 0.94-3.30) and hypertension (OR: 1.50; 95% CI 0.81-2.79) did not reach statistical significance. TG/HDL ratio was associated to first coronary event in all categories of BMI6.
A number of studies have shown that the ratio TG/HDL has a good correlation with the generally accepted methods to define insulin sensitivity, with the possible exception of African Americans7. Some drugs (thiazolidindiones, angiotensin and aldosterone antagonists, moxonidine) have demonstrated favourable effects on IR, although we do not have enough data to confirm if TG/HDL also changes in the good direction. Fig 1 :TG/HDL ratio correlated with the incidence of coronary event in the MESYAS study
1. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009 May-Jun;2(5-6):231-7. 2. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009 Oct 20;120(16):1640-5. 3. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E15-26. 4. Pfützner A, Weber MM, Forst T. A biomarker concept for assessment of insulin resistance, beta-cell function and chronic systemic inflammation in type 2 diabetes mellitus. Clin Lab. 2008;54(11-12):485-90. 5. Cordero A, Laclaustra M, León M, Casasnovas JA, Grima A, Luengo E, Ordoñez B, Bergua C, Bes M, Pascual I, Alegría E; MESYAS Registry Investigators. Comparison of serum lipid values in subjects with and without the metabolic syndrome. Am J Cardiol. 2008 Aug 15;102(4):424-8. 6. Cordero A, Andrés E, Ordóñez B, León M, Laclaustra M, Grima A, Luengo E, Moreno J, Bes M, Pascual I, Civeira F, Pocovi M, Alegría E, Casasnovas JA. Usefulness of triglycerides-to-high-density lipoprotein cholesterol ratio for predicting the first coronary event in men. Am J Cardiol 2009 Nov 15;104(10):1393-7. 7. Kim-Dorner SJ, Deuster PA, Zeno SA, Remaley AT, Poth M. Should triglycerides and the triglycerides to high-density lipoprotein cholesterol ratio be used as surrogates for insulin resistance?Metabolism. 2009 Sep 29. [Epub ahead of print]