TRIGLYCERIDE/HIGH-DENSITY LIPOPROTEIN CHOLESTEROL CONCENTRATION RATIO IDENTIFIES ACCENTUATED CARDIO-METABOLIC RISK

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP14479.OR TRIGLYCERIDE/HIGH-DENSITY LIPOPROTEIN CHOLESTEROL CONCENTRATION RATIO IDENTIFIES ACCENTUATED CARDIO-METABOLIC RISK John Armato MD 1, Gerald Reaven MD 2, Ronald Ruby MD 1 From: 1 Providence Little Company of Mary Cardiometabolic Center, Torrance CA Division of Cardiovascular Medicine Falk CVRC, Stanford Medical Center 300 Pasteur Drive Stanford, California, Running title: TG/HDL-C ratio and cardio-metabolic risk Correspondence Address: Dr. John Armato Providence Little Company of Mary Medical Center Cardiometabolic Center 4101 Torrance Blvd Torrance, CA Dr.armato@gmail.com

2 No financial support was provided in the generation of this manuscript Abstract word count: 238 Article word count: 1962 Number of tables: 4 Abstract Purpose: Plasma triglyceride/high-density lipoprotein cholesterol ratios (TG/HDL-C) have been shown to identify apparently healthy individuals at increased cardio-metabolic risk. This study evaluates the utility of this approach in patients at risk of developing diabetes. Methods: Individuals (n=1010) in a private practice identified at increased risk of type 2 diabetes (T2DM) by American Association of Clinical Endocrinologist criteria, were evaluated. Subjects had measurements of body mass index (BMI), blood pressure (BP), lipid/lipoprotein concentrations, highly sensitive C-reactive protein (hs-crp), and glucose, insulin and c-peptide concentrations during a 75gm, glucose challenge. The TG/HDL-C ratio was used to stratify individuals into high (highest quartile) vs. low (lowest 3 quartiles) risk categories.

3 Results: TG/HDL-C ratios identifying the highest quartile differed in men ( 3.0) and women ( 2.0). Using these cut-points, the high risk group for men and women had significantly higher BP, a more adverse lipid profile, was more insulin resistant as assessed by HOMA- IR, or the Matsuda index and had higher hs-crp concentrations for men and women. Combined, approximately 25% of highest quartile patients expressed values 3.0 mg/dl. Conclusion: The TG/HDL-C ratio provides a simple approach to identify individuals at accentuated cardio-metabolic risk within a population of perceived increased risk of T2DM. This was particularly the case as regards the presence of insulin resistance. Given the many syndromes associated with insulin resistance, including T2DM and coronary heart disease, an elevated TG/HDL-C ratio supports more aggressive efforts to enhance insulin sensitivity. Abreviations: TG = Triglyceride concentration (plasma); HDL-C = High-density lipoprotein cholesterol; T2DM = Type 2 Diabetes; CVD = Cardiovascular disease; BMI = Body mass index; HbA1c = Glycohemoglobin; LDL-C = Low-density lipoprotein cholesterol; Hs-CRP = Highsensitivity C-reactive protein; OGTT = Oral glucose tolerance test; NGT = Normal glucose tolerance; IFG = Impaired fasting glucose; IGT = Impaired glucose tolerance; IFG/IGT = Combined Impaired fasting glucose and impaired glucose tolerance; FPI = Fasting plasma insulin; HOMA-IR = Homeostatic model assessment insulin resistance; MetS = Metabolic syndrome. Introduction Previous studies have shown that the plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is significantly correlated with a direct measure of insulin-mediated glucose disposal [1], and is able to identify insulin resistance and enhanced cardio-metabolic risk, including the development of type 2 diabetes [T2DM]

4 and cardiovascular disease (CVD) in presumably healthy individuals [2-4]. More recently, a population-based study, based on a health check program in Japan, has shown that an elevated TG/HDL-C ratio can also predict chronic kidney disease [5]. The suggestion that the plasma TG/HDL-C ratio can help identify insulin resistance and increased cardiometabolic risk in presumably healthy individuals does not mean that the same relationship and TG/HDL-C thresholds would hold true for patients already identified as at increased risk for the development of cardio-metabolic disease, specifically, T2DM. The present analysis was performed to address this issue by evaluating the efficacy of the TG/HDL-C ratio as a simple way to identify insulin resistance and enhanced cardio-metabolic risk in individuals already deemed to be at increased risk for developing T2DM by criteria outlined in a Consensus Statement of the American College of Endocrinology and the American Association of Clinical Endocrinologists [6]. Material and Methods All participants (n=1326) were individuals evaluated in an Internal Medicine/Endocrinology Practice in Southern California who had been identified as at risk for developing diabetes based upon exhibiting 1 of the American Association of Clinical Endocrinology Consensus Criteria [6]. These criteria include: family history of T2DM in a first degree relative, history of gestational diabetes, delivery of a baby weighing more than 4.1 kg, polycystic ovary syndrome, premature coronary artery disease, increased plasma triglyceride (>200 mg/dl), low HDL-C cholesterol (<40 mg/dl in males and <50 in females), previously identified impaired fasting glucose or impaired glucose tolerance, metabolic

5 syndrome, obesity as assessed by body mass index (BMI) 30 kg/m 2, HbA1c > 5.7%, fatty liver, sleep apnea, or acanthosis nigricans. Height, weight, BMI and blood pressure were determined. After an overnight fast measurements were made of fasting plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, TG, TG/HDL-C ratio, uric acid, high-sensitivity C-reactive protein (hs-crp), and hemoglobin A1C (HbA1c) concentrations. Patients then underwent a 75 gram oral glucose tolerance test (OGTT) with measurement of plasma glucose (PG), insulin (PI), and C-peptide concentrations at 0, 30, 60, and 120 minutes. Blood samples were immediately centrifuged and plasma frozen at -20 C until analyzed. All assays were performed at Providence Little Company of Mary Medical Center, Torrance Clinical Laboratories (Torrance, CA). American Diabetes Association criteria [7] were utilized to classify individuals as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), combined IFG/IGT, or T2DM. Of the initial 1326 subjects, 76 had T2DM by OGTT criteria and complete data were not available in 240 individuals leaving data from1010 subjects to be analyzed. Based upon prior prospective data showing that the 25 % of the population that was most insulin resistant was at increased risk to develop glucose intolerance, hypertension, or CVD [8], the TG/HDL-C concentration ratios that separated those in the highest quartile from the remainder of the population were determined separately for men and women. These values

6 are seen in Table 1, and led us to classify as being at high cardio-metabolic risk those whose TG/HDL-C ratios were 3.0 or 2.0 in men and women, respectively. Insulin resistance was estimated by 3 surrogate measurements: FPI concentration (fasting plasma insulin), HOMA-IR, and the Matsuda index. HOMA-IR [9] was calculated as: (fasting FPI/18) x (fasting PG/22.5), with fasting FPG as mg/dl and fasting PI as (mu/l), and the Matsuda Index [10] was calculated as: 10,000 / (fasting PG x fasting PI x mean PG x mean PI) 0.5. Individuals whose values for the Matsuda index placed them in the lower quartile were classified as being insulin resistant. Data from men and women were analyzed separately. Cardiovascular and biomedical measures in the high and low risk groups were compared utilizing a two tailed t-test with StatPlus software, with significance set at p<0.05. The statistical analysis of OGTT response of patients above and below diagnostic cut-points suggested by the American Diabetes Association [7] was assessed by Chi-Square analysis utilizing Microsoft Excel. Results Table 2 compares demographic and a number of cardio-metabolic risk factors in men and women, divided on the basis of their plasma TG/HLD-C concentration ratios. Focusing initially on men, the results in the left panels of Table 2 demonstrate that every cardiometabolic risk factor, with the exception of uric acid concentration, was significantly accentuated in those with a TG/HDL-C 3.0. A similar generalization can be applied to the findings in women (right panels), in that every risk factor was significantly more adverse in those with a TG/HDL-C ratio 2.0. Indeed, the quantitative difference between individual risk factors in the two HDL-C groups was generally greater in magnitude in the women. The HDL-C concentrations in the women were also of interest in terms of the actual values.

7 Thus, mean HDL-C concentration in those with an elevated TG/HDL-C ratio was > 50 mg/dl, with a somewhat surprisingly high mean concentration of 72 mg/dl in those with a TG/HDL-C ratio < 2.0. We have no obvious explanation for why these values are so relatively high, other than that the population served by this institution is interested in a healthy life-style, perhaps best reflected by the fact the mean BMI was <25.0 kg/m² in the women with a TG/HDL-C ratio <2.0. The ability of the TG/HDL-C ratio to identify a more adverse glycemic state is evaluated in Table 3, and the data emphasize its efficacy in several ways. Firstly, and most dramatically, an elevated TG/HDL-C ratio in both men ( 3.0) and women ( 2.0) identified those individuals whose estimates of insulin resistance were increased approximately 2-fold, and this was true irrespective of how it was quantified FPI, or HOMA-IR, or Matsuda index. The ability of the TG/HDL-C ratio to identify those at enhanced glycemic risk also seemed to be more the case in women. Thus, prediabetes was approximately twice as common in women whose TG/HDL-C ratio was 2.0 (53% vs. 33%), and the prevalence of combined impaired fasting glucose and impaired glucose tolerance was also much greater in this subset of women with prediabetes (29%vs.16 %). Furthermore, fasting plasma glucose concentrations and hemoglobin A1c concentrations were somewhat higher in the women with the higher TG/HDL-C ratios. Finally, the criteria used to identify the experimental population [6] were such that substantial numbers were being treated with various pharmacological agents as listed in Table 4. Statins and various blood pressure lowering drugs were prescribed for about half of the population, and the pattern of drug treatment seemed reasonably comparable across the

8 4 experimental populations. It should noted that only a small proportion of the population were receiving fibrates, niacin, or ezetimibe. Discussion Perhaps the best way to put the findings of this study in perspective would be to focus on answering a series of questions. Firstly, does use of the TG/HDL-C ratio identify insulin resistance and accentuated risk of cardio-metabolic disease in individuals already classified at increased risk for developing T2DM? Given the results in Tables 2 and 3, the answer seems to be yes. Thus, essentially every cardio-metabolic risk factor was significantly more untoward in participants with an elevated TG/HDL-C ratio, although the impact seemed somewhat quantitatively greater in women. A second issue requiring discussion is the clinical utility of identifying individuals enrolled in this study at being at accentuated CVD risk on the basis of an elevated TG/HDL-C ratio. Thus, although cardio-metabolic risk profiles were significantly more untoward in men and women with a ratio 3.0 and 2.0, respectively, how clinically useful is this information? Perhaps the best example of the utility of this approach is its ability to identify individuals at enhanced risk to develop T2DM. Insulin resistance is an independent predictor of T2DM [11, 12], and irrespective of the index used, FPI concentration, HOMA-IR, or the Matsuda index, estimates of insulin resistance were increased approximately two-fold in individuals with an

9 elevated TG/HDL-C ratio. The increased likelihood of developing T2DM is particularly striking in women with an elevated TG/HDL-C ratio, in whom the OGTT results show that prediabetes was present in 53% as compared to a prevalence of 33 % in women whose TG/HDL-C ratio is <2.0. Given this information, it would seem prudent for health care providers to more aggressively pursue life-style changes, diet and physical activity, known to decrease risk of T2DM [13]. There are other changes in cardio-metabolic risk factors in those with an elevated TG/HDL-C ratio that are not as dramatic, but also suggest the need for more aggressive clinical intervention in these individuals. For example, although essentially all cardio-metabolic risk factors measured were significantly more abnormal in those with an elevated TG/HDL-C ratio, the differences in concentrations of non-hdl-c and hs-crp are particularly worth noting, with approximately 25 % of those with an elevated ratio having an hs- CRP concentration 3 mg/dl. A third question that needs to be addressed is how to place the current findings in the context of previous studies evaluating the clinical utility of determining the plasma TG/HDL- C concentration ratio [1-4]. This approach was introduced in an effort to find a relatively simple way to identify insulin resistant, apparently healthy individuals, who were at increased cardio-metabolic risk as result of the defect in insulin action [1-3], At that time it was argued that direct measurements of insulin action were not practical at a clinical level, and that surrogate estimates that relied on measurements of insulin concentration, i.e., fasting and/or post-glucose load insulin concentrations [8], HOMA-IR [9], Matsuda index [10], etc., could not lead to specific cut-point values with which to stratify individuals in the absence of a standardized assay [15]. Since its introduction, evidence has been published that the TG/HDL-C ratio is able to identify cardio-metabolic risk and outcome in apparently

10 healthy individuals as effectively as use of the more complicated metabolic syndrome diagnostic criteria [1-4]. However, to the best of our knowledge, the TG/HDL-C ratio has not been used to identify accentuated risk in individuals already judged to be at increased risk by a number of more conventional criteria [6]. The results seen in Tables 2 and 3 seem to support the notion that stratifying a population thought to be at high cardio-metabolic risk on the basis of their TG/HDL-C concentration continues to provide useful risk factor information. Although the experimental findings are straight-forward, there are several important caveats that must be expressed to put the results into a clinical context. To begin with, the patient population had already been identified as being at increased risk of developing diabetes and therefore at increased cardio-metabolic risk, and it could be argued that any refinement of that state resulting from use of the TG/HDL-C ratio is of little added value. In addition, the patient population was primarily of European ancestry, and caution should be exercised before extrapolating to any other racial group. For example, it is highly likely that the specific TG/HDL-C ratios used in this study would not be appropriate to apply to an African-American population [16]. In that context, TG/HDL-C ratios used in earlier studies to predict insulin resistance and increased cardio-metabolic risk in apparently healthy individuals were somewhat different, with values of 3.5 and 2.5, respectively in men and women [2, 3]. The lower TG/HDL-C cut-points which identified high risk individuals in this study may simply be a reflection of the fact that approximately 50 % of the subjects were taking drugs that affect plasma lipid/lipoprotein concentrations as compared to none in the earlier studies. In support of this notion is that although the absolute cut-points (2.0 and 3.0) were lower in this study, the sensitivity (~45%) and specificity (~85%) with which these

11 values identified insulin resistant individuals were quite comparable to what was achieved using values of 2.5 and 3.5 in an earlier study [2]. Whether or not this is the explanation remains to be seen, but should be taken into consideration by health care providers who plan to use the ratio. It should also be noted that the values used to compute the TG/HDL-C ratio are 2 of the 5 criteria used to make a diagnosis of the metabolic syndrome MetS; a diagnostic category that has been widely used to identify individuals at increased cardiometabolic risk [7]. Although not as extensively studied, in head-to head comparisons the TG/HDL-C ratio performs comparably to the MetS in the ability to identify apparently healthy individuals who are insulin resistant, with a more adverse cardio-metabolic risk profile, and who go on to develop CVD [2, 3, 18, 19]. On the other hand, although there is evidence that the TG/HDL-C ratio offers a simple way to identify enhanced cardio-metabolic risk and adverse outcomes, no interventional studies have been conducted to see if its use would lead to clinical benefit. Finally, as with any clinical algorithm, the health care provider must still exercise clinical judgment as how best to utilize, if at all, the TG/HDL-C ratio. For example, a very high TG/HDL-C ratio, associated with an extremely high TG and normal HDl-C concentration, suggests the presence of lipoprotein lipase deficiency, a unique clinical syndrome. Similarly, a low TG/HDL-C ratio in a person treated with fibrates or niacin does not mean that the patient is not at risk of T2DM or CVD. Put most simply, use of the TG/HDL-C ratio to estimate cardio-metabolic risk must depend upon the judgment of the individual clinician as to whether the information it provides will aid in the care of the individual patient. Conflict of Interest

12 The authors state that there are no conflicts of interest to report. References 1. McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to identify insulinresistant individuals at increased risk of cardiovascular disease? Am J Cardiol 2005; 96: Salazar MR, Carbajal HA, Espeche WG, et al. Relation among the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio, insulin resistance, and associated cardio metabolic risk factors in men and women. Am J Cardiol 2012;109: Salazar MR, Carbajal HA, Espeche WG, et al. Cardiovascular disease risk and outcome: Use of the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio versus metabolic syndrome criteria. J Int Med 2013; 273: Vega GL, Barlow CE, Grundy SM, Leonard D, DeFina LF. Triglyceride-to-high-densitylipoprotein-cholesterol ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men. J Investig Med. 2014;62:

13 5. Tsuruy K, Yoshida H, Nagata M, et al. Association of the triglyceride to high-density lipoprotein cholesterol ratio with the risk of chronic kidney disease: Analysis in a large Japanese population. Atherosclerosis 2014; 233: Garber AJ, Handelsman Y, Einhorn D, et al. Diagnosis and management of prediabetes in the continuum of hyperglycemia when do the risks of diabetes begin? A consensus statement from the American College of Endocrinologists and the American Association of Clinical Endocrinologists. Endocrine Practice 2008; 14: American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care 2013; 36( Suppl 1): S Zavaroni I, Bonini L, Gasparini P, et al. Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: The Barilla factory revisited. Metabolism. 1999; 48: Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37: Lillioja S, Mott, DM, Spraul M. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:

14 13. The Diabetes Prevention Program. Description of lifestyle intervention. Diabetes Care 2002; , 14. Knowles JW, Assimes TL, Tsao PS, et al. Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism 2013; 62: Reaven GM. Wanted! A standardized measurement of plasma insulin concentration. Arterioscler Thromb Vasc Biol 2011;31: Reaven G, McLaughlin T. Why the Plasma TG/HDL-C Concentration Ratio Does Not Predict Insulin Resistance in African Americans. Arch Intern Med 2006;166: Alberti KG, Eckel RH, Grundy SM, et al. 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 ;120: Salazar MR, Carbajal HA, Espeche WG,et al. Comparison of the abilities of the plasma triglyceride/high-density lipoprotein cholesterol ratio and the metabolic syndrome to identify insulin resistance. Diab Vasc Dis Res. 2013;10: Salazar MR, Carbajal HA, Espeche WG, et al. Use of the plasma triglyceride/highdensity lipoprotein cholesterol ratio to identify cardiovascular disease in hypertensive subjects. J Am Soc Hypertens. 2014;8:724-31

15 Table 1. Distribution of TG/HDL-C Plasma Concentration Ratios by Quartiles Women (N=412) Men (N=598) Mean±SD Minimum Maximum Mean±SD Minimum Maximum Quartile ± ± Quartile ± ± Quartile ± ± Quartile ± ± TG/HDL-C=Triglyceride/High density lipoprotein concentration.

16 Table 2 Mean (±SD) Demographic and Metabolic Characteristics Women Men N=321 N=91 T-test N=469 N=129 T-test TG/HDL-C <2.0 >2.0 p value <3.0 >3.0 p value Age (yrs) 56 (±12) 58 (±12) NS 57 (±12) 53 (±11) < BMI (Kg/m2) 24.7 (±5.0) 28.8 (±5.3) < (±3.9) 29.2 (±4.3) < SBP (mm Hg) 119 (±14) 126 (±15) < (±14) 127 (±15) 0.05 DBP (mm Hg) 71 (±8) 75 (±10) < (±9) 78 (±10) <0.001 Cholesterol (mg/dl) 186 (±32) 204 (±50) < (±34) 188 (±43) < TG (mg/dl) 77 (±22) 184 (±126) < (±27) 215 (±89) < HDL-C (mg/dl) 72 (±15) 54 (±8) < (±12.4) 44 (±9) < Non-HDL-C (mg/dl) 113 (±27) 150 (±47) < (±30) 143 (±39) < CRP-hs (mg/l) 1.9 (±3.1) 2.8 (±3.5) < (±2.5) 2.2 (3.0) <0.05 Uric Acid (mg/dl) 4.7 (±1.2) 5.3 (±1.2) < (±1.3) 6.4 (±1.5) NS SD=Standard Deviation, BMI=Body mass index, SBP=Systolic blood pressure, DBP=Diastolic blood pressure, TG=Triglycerides, HDL-C= High density lipoprotein concentration, Non-HDL- C=Non high density lipoprotein concentration, CRP-hs=C-reactive protein highly sensitive, T- test=two-tailed t-test.

17 Table 3 Glycemic Variables (Mean±SD) WOMEN MEN N=321 N=91 T-TEST N=469 N=129 T-TEST TG/HDL <2.0 >2.0 p-value <3.0 >3.0 p-value FPG (mg/dl) 94 (±9) 98 (±12) < (±9) 98 (±10) NS FPI (mu/l) 6.6 (±6.1) 12 (±8.9) < (±7.2) 13.3 (±10.9) < A1c (%) 5.5 (±0.4) 5.6 (±0.4) < (±0.4) 5.5 (±0.4) NS HOMA-IR 1.6 (±1.5) 3 (±2.3) < (±1.7) 3.3 (±3.0) < MATSUDA INDEX 7.43 (±5.25) 3.96 (±2.60) < (±4.56) 3.59 (±2.00) < OGTT: NGT (%) OGTT: Pre-DM (%) < * NS * FPG=Fasting plasma glucose, FPI=Fasting plasma insulin, A1c=Hemoglobin A1c, OGTT: NGT=Oral glucose tolerance test: Normal glucose tolerance, OGTT: Pre-DM=Oral glucose tolerance test: Prediabetes. * Chi-Square test.

18 TABLE 4. Prevalence of pharmacological treatment Women Men N=321 N=91 N=469 N=129 Pharmacologic Agent TG/HDL-C<2.0 TG/HDL-C>2.0 TG/HDL-C<3.0 TG/DHL-C>3.0 Statin (%) ACE-I (%) ARB (%) CCB (%) Fibrate (%) Niacin (%) Thiazide (%) Ezetimibe (%)