Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk

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1 credits vilble for this rticle see pge 96. Study of the Use of Lipid Pnels s Mrker of Insulin Resistnce to Determine Crdiovsculr Risk Ruth Ann Bertsch, MD, PhD, FACP; Mqdood A Merchnt, MSc, MA ABSTRACT Context: When ssessing the lipid pnel, prcticl physicins tend to focus on the low-density lipoprotein cholesterol (LDL-c). However, n elevted triglyceride/ high-density lipoprotein cholesterol (HDL-c) rtio, suggesting insulin resistnce, lso effectively predicts crdiovsculr outcomes but requires different tretments thn n elevted LDL-c. We tested whether high triglyceride/hdl-c rtios re ssocited with more risk thn high LDL-c concentrtions or other lipid mrkers of therogenicity. Methods: We followed 103,646 members ged 50 to 75 yers without crdiovsculr disese or dibetes in community helth pln. Subjects were ctegorized s insulin sensitive or insulin resistnt on the bsis of triglyceride nd HDL-c in the index yer. The primry outcome ws ischemic hert disese. The percentge of subjects with primry outcome fter 8 yers ws strtified by insulin ctegory, lipid mesures, nd blood pressure. Hzrd rtios (HR) for insulin resistnce, LDL-c, ge, sex, nd the presence of hypertension were determined in multivrite nlysis. Results: Subjects with insulin resistnce but lipid mesures helthier thn the medin hd worse outcomes thn those who were insulin sensitive but hd unhelthier lipid mesures such s non-hdl-c nd the rtios of totl cholesterol/hdl-c nd LDL-c/ HDL-c. The HR for 60 mg/dl increse in LDL-c ws 1.14 (95% confidence intervl [CI], ); the HR for n LDL-c greter thn 160 mg/dl ws 1.19 (95% CI, ). In contrst, the hzrd rtio for hving n insulin-resistnt triglyceride/hdl-c rtio ws 1.68 (95% CI, ), compred with n insulin-sensitive rtio. There ws no difference in outcomes between insulin-resistnt but normotensive ptients nd insulin-sensitive but hypertensive ptients. Conclusion: Insulin resistnce, s mnifested by high triglyceride/hdl-c rtio, ws ssocited with dverse crdiovsculr outcomes more thn other lipid metrics, including LDL-c, which hd little concordnce. Physicins nd ptients should not overlook the triglyceride/hdl-c rtio. INTRODUCTION Predicting ptients risk for crdiovsculr disese (CVD) is n importnt function of medicine. The risks of high concentrtions of low-density lipoprotein cholesterol (LDL-c) re well recognized. Tretment of LDL-c with 3-hydroxy-3-methylglutryl-coenzyme A reductse inhibitors (sttins) reduces the incidence of myocrdil infrctions. 1 Both the number of LDL-c mesurements in high-risk ptients nd the percentge of those whose LDL-c is below 100 mg/dl were used until 2015 s qulity metrics for helth cre fcilities. 2-4 Until the ltest 2013 cholesterol guidelines dvocted tht we dose sttins ccording to overll CVD risk, we were encourged to dose sttins ccording to the bsolute LDL-c concentrtion. 5 So, until recently, busy, prcticing physicins were encourged to focus on the LDL-c. Other components of the lipid pnel provide informtion for ssessing CVD risk, lthough these risk fctors re not well understood by mny physicins. For exmple, the rtio of triglycerides to high-density lipoprotein cholesterol (HDL-c) reflects the presence of insulin Perm J 2015 Fll;19(4): resistnce. A rtio greter thn 3.0 hs been mesured s 64% sensitive nd 68% specific for insulin resistnce compred with the gold stndrd insulin suppression test. 6 The extreme mnifesttion of insulin resistnce is better known s the metbolic syndrome. 7 Insulin resistnce develops in the presence of both genetic predisposition nd excess diposity usully frnk obesity. 8,9 The resulting insulin resistnce is ssocited with much hypertension, dibetes, therosclerosis nd its complictions, nd even mny cncers. 9 In ddition to being good mesure of insulin resistnce, the rtio of triglycerides to HDL-c is powerful predictor of CVD Yet insulin resistnce, even when mnifested by the metbolic syndrome, is often unrecognized in clinicl prctice The only Americn study tht showed good recognition of the metbolic syndrome ws bsed on survey with only 30% response rte. 17 Furthermore, the best tretment for insulin resistnce is weight loss nd exercise, yet neither the Joint Commission nor the principl evlutor of the qulity of Americn hospitls (Helthcre Effectiveness Dt nd Informtion Set) mentions exercise. The mesures of the Helthcre Effectiveness Dt nd Informtion Set only recently strted requiring tht body mss index be documented for frction of dults. 18 Mny physicins do not even discuss obesity with their obese ptients. 19,20 When reviewing the lipid pnel, physicins often ddress the LDL-c but neglect the triglyceride nd HDL-c rtio. Yet, multiple smll nd modertely sized studies suggest tht the triglyceride to HDL-c rtio is more predictive of crdiovsculr events thn the LDL-c, Ruth Ann Bertsch, MD, PhD, FACP, is Hospitlist t the Scrmento Medicl Center in CA. E-mil: ruth.nn.bertsch@kp.org. Mqdood A Merchnt, MSc, MA, is Senior Dt Consultnt in the Division of Reserch in Oklnd, CA. E-mil: mqdood.merchnt@kp.org. 4 The Permnente Journl/ Fll 2015/ Volume 19 No. 4

2 Study of the Use of Lipid Pnels s Mrker of Insulin Resistnce to Determine Crdiovsculr Risk non-hdl-c, totl cholesterol/hdl-c rtio, nd LDL-c/HDL-c rtio We undertook lrge, retrospective study to ssess which metric better predicts the risk of ischemic hert disese mong members of n Americn community Helth Pln, Kiser Permnente Northern Cliforni (KPNC). METHODS Ptient Selection We conducted retrospective cohort study mong members of KPNC, nonprofit, prepid Helth Pln tht serves more thn 3 million people. 25 The Kiser Foundtion Reserch Institute s institutionl review bord pproved this study nd wived informed consent. Inclusion criteri were dults ge 50 to 75 yers, the presence of fsting lipid pnel in the yer 2000, minimum of 12 months continuous membership in the yer before the index lipid pnel, nd t lest 10 months of membership in ech of the 3 yers preceding the yer before the index lipid pnel. Exclusion criteri were members who hd triglycerides greter thn 400 mg/dl, who were prescribed t lest 180-dy supply of sttin in the yer before the lipid pnel, who hd dibetes before the index lipid pnel, or who hd evidence of significnt therosclerosis (Figure 1). Refer to Tble 1 (vilble online t: org/files/fll2015/icd9.pdf) for the Interntionl Sttisticl Clssifiction of Diseses, Ninth Revision, codes describing the inclusion, exclusion, nd censorship criteri. Ptients not meeting criteri for insulin resistnce or insulin sensitivity were put in single intermedite ctegory. The dignosis of hypertension required tht primry cre clinicin hd included hypertension s dignosis for t lest two visits in the two yers before the lipid pnel or one visit in the previous two yers coupled with one of the following: 1) one or more inptient hypertension dignoses in the pst two yers; 2) filled prescription for hypertension mediction in the previous six months; or 3) history of dibetes, CVD, hert filure, or stroke. Sttisticl Anlysis For the bivrite nlysis, we excluded ptients with gp of more thn 4 months in membership. Thus, we included only ptients who hd died of ischemic hert disese during the 8 yers fter the first lipid pnel in 2000 or ptients who hd 8 yers of complete follow-up from the time of the first lipid pnel in 2000 (n = 80,328). We used χ 2 nlysis to look for differences in the primry outcome of ischemic hert disese mong the 3 insulin groups, strtified by vrious prmeters of the lipid pnel or hypertension. The lipid Definitions of Outcomes nd Risk Fctors The primry outcome ws ny ischemic hert disese (Interntionl Sttisticl Clssifiction of Diseses, Ninth Revision, codes 410 through 414), including deth cused by ny of those codes fter the index lipid pnel. The ptient ws deemed insulin resistnt if the triglyceride level ws in the highest tertile of the cohort nd the HDL-c ws in the lowest tertile of the cohort. The ptient ws deemed insulin sensitive if the triglyceride level ws in the lowest tertile of the cohort nd the HDL-c level ws in the highest tertile. Figure 1. Qulity of reporting of met-nlyses sttement flow digrm. Selection of the cohorts for univrite nd bivrite nlyses. Avilble from: ICD-9 = Interntionl Sttisticl Clssifiction of Diseses, Ninth Revision. The Permnente Journl/ Fll 2015/ Volume 19 No. 4 5

3 Study of the Use of Lipid Pnels s Mrker of Insulin Resistnce to Determine Crdiovsculr Risk prmeters were dichotomized t the medin vlues of the cohort. The Fisher exct test ws used to compre the incidence of ischemic hert disese between the 2 min groups of interest: those with insulin resistnce but lipid or blood pressure mesures below the medin, nd those with insulin sensitivity but lipid or blood pressure mesures bove the medin. The results were djusted for multiple comprisons using the permuttion method; p vlues < 0.05 indicted significnt difference. The Cox proportionl hzrd model ws used for the multivrite nlysis. Our outcome vrible ws gin dignosis of ischemic hert disese or deth therefrom subsequent to the first lipid pnel in The min predictors were insulin resistnce nd LDL-c; covrites included sex, ge (per yer), nd being hypertensive. The full cohort of 103,646 people ws included in the nlysis with follow-up ending t deth; orgn trnsplnt; dignosis of end-stge renl disese; dignosis of or deth resulting from CVD; gp of more thn 4 months of membership; or December 31, 2008, whichever cme first. We tested the proportionl hzrd ssumptions for our min predictors, insulin resistnce nd LDL-c, using Schoenfeld residuls becuse our lrge smple size ws not conducive to using the computing-intensive Mrtingle residuls. Neither vrible violted the proportionl hzrd ssumption. RESULTS Tble 2 describes the finl cohort of 103,646 ptients: 16.7% were insulin resistnt nd 17.8% were insulin sensitive. The cutoff lipid vlues of the insulin resistnt group turned out to be 176 mg/dl for the triglycerides nd 46 mg/dl for the HDL-c. For the insulin sensitive group, the cutoffs were 112 mg/dl triglycerides nd 60 mg/dl HDL-c. The distribution of insulin responsiveness vried significntly by ge, sex, self-identified rce, blood pressure, nd vrious lipid vlues. Men were more insulin resistnt thn women. Insulin resistnce ws ssocited with high blood pressure, s expected. 26,27 For the popultion with t lest 8 yers of follow-up (n = 80,328), the incidence of ischemic hert disese ws significntly higher in insulin-resistnt ptients with lower LDL-c (17.7%) thn in insulin-sensitive ptients with higher LDL-c (10.0%) (p < 0.001; Figure 2). Similrly, insulin-resistnt ptients with lower LDL-c/HDL-c rtio hd significntly higher incidence of ischemic hert disese (16.2%) thn insulin-sensitive ptients with higher LDL-c/HDL-c rtio (9.96%) (p < 0.001; Figure 3). A similr pttern emerged with totl cholesterol/hdl-c nd non-hdl-c (Tble 3). Thus, being insulin resistnt crried significntly Tble 2. Cohort chrcteristics by degree of insulin responsiveness Chrcteristic Insulin sensitive (n = 18,418) Indeterminte insulin sensitivity (n = 67,878) Insulin resistnt (n = 17,350) Totl popultion (N = 103,646) p vlue Age, men yers (SD) 60.3 (7.1) 60.5 (7.1) 59.8 (7.0) 60.3 (7.1) < Sex, % Mle < Femle Rce, % White < Asin Blck Hispnic Other/unknown Blood pressure, % Normotensive < Hypertensive Lipid vlues, men (SD) LDL-c, mg/dl 134 (34) 146 (35) 140 (37) 143 (36) < b Triglycerides/HDL-c 1.1 (0.3) 2.9 (1.2) 6.7 (2.0) 3.2 (2.1) < b Totl cholesterol, mg/dl c 225 (36) 231 (41) 230 (38) 230 (40) < b Triglycerides, mg/dl c 80 (19) 152 (61) 255 (60) 157 (76) < b HDL-c, mg/dl 75 (13) 54 (12) 39 (4) 55 (16) < b Totl cholesterol/hdl-c 3.1 (0.6) 4.4 (1.0) 6.0 (1.1) 4.4 (1.3) < b Non-HDL cholesterol, mg/dl 150 (35) 176 (39) 191 (37) 174 (40) < b LDL-c/HDL-c 1.8 (0.6) 2.8 (0.9) 3.6 (1.0) 2.8 (1.0) < b p vlues were clculted using the χ2 test. b p vlues were clculted using the Generl Liner Model. c SI conversion fctors: To convert cholesterol vlues to millimoles per liter, multiply by To convert triglycerides to millimoles per liter, multiply by HDL-c = high-density lipoprotein cholesterol; LDL-c = low-density lipoprotein cholesterol; SD = stndrd devition. 6 The Permnente Journl/ Fll 2015/ Volume 19 No. 4

4 Study of the Use of Lipid Pnels s Mrker of Insulin Resistnce to Determine Crdiovsculr Risk 68% risk of ischemic hert disese for insulin-resistnt ptients is much higher thn the LDL-c in both models. For every 1 yer of incresed ge, person ws 5.9% more likely to develop ischemic hert disese, ssuming ll other mesured vribles did not chnge. This does not scle linerly with dditionl yers (becuse the hzrd rtio is the exponent of bet [the point estimte] for ge in the model). Figure 2. Incidence of ischemic hert disese (IHD) strtified by insulin resistnce nd low-density lipoprotein cholesterol (LDL-c). Insulin resistnce nd low LDL-c ( 3.66 mmol/l [142 mg/dl]) ws ssocited with higher incidence of IHD thn insulin sensitivity nd high LDL-c (p < 0.001, Fisher exct test). Error brs show the 95% confidence limits. Figure 3. Incidence of ischemic hert disese (IHD) strtified by insulin resistnce nd the low-density lipoprotein cholesterol (LDL-c)/high-density lipoprotein cholesterol (HDL-c) rtio. Insulin resistnce nd low LDL-c/HDL-c rtio (less thn or equl to 2.69) ws ssocited with higher incidence of IHD thn insulin sensitivity nd high LDL-c/HDL-c rtio (p < 0.001, Fisher exct test). Error brs show the 95% confidence limits. higher risk of ischemic hert disese thn hving n LDL-c, LDL-c/HDL-c, totl cholesterol/hdl-c, or non-hdl-c cholesterol higher thn the medin vlues of 142 mg/dl, 2.69, 4.30, nd 173 mg/dl, respectively. However, there ws no difference in the incidence of ischemic hert disese between insulinresistnt but normotensive ptients nd insulin-sensitive but hypertensive ptients (Tble 3). For the full cohort of 103,646 ptients, the men follow-up ws 7 yers (medin, 8.3 yers). We rn 2 models; in the first we used LDL-c s ctegoricl vrible using LDL-c 100 mg/dl s the reference nd compred this with both the LDL-c between 101 mg/dl nd 160 mg/dl nd the LDL-c 161 mg/dl. In the second model we used LDL-c s continuous vrible nd clculted the hzrd rtio on the bsis of increses in increments of 60 mg/dl. Both models give identicl results for mle sex, hypertension, ge, nd insulin resistnce. All conferred 60% to 72% greter risk of ischemic hert disese thn femle sex, hving norml blood pressure, nd being insulin sensitive, respectively (Tble 4). In contrst, LDL-c > 160 mg/dl conferred 19% risk. In the second model 60-mg/dL increse in LDL-c conferred 14% greter risk of developing ischemic hert disese. The DISCUSSION In this lrge-scle nlysis of members of Helth Pln, we found tht insulin resistnce, s defined by high triglycerides nd low HDL-c, ws more predictive of ischemic hert disese thn LDL-c mong 50 to 75 yer olds who hd not hd mjor crdiovsculr event or cquired dibetes. Also, the people in the worst tertile of triglycerides nd HDL-c hd worse ischemic hert disese thn those with elevted non-hdl-c, totl cholesterol/hdl-c rtios, or LDL-c/HDL-c rtios. Our popultion provides severl dvntges. First, it is community cohort, not study group, which my enble the results to pply more generlly. Second, the cohort is ethniclly heterogeneous. Third, it is lrge popultion; more thn 100,000 individuls were included in this study. Finlly, lrge study in n Americn popultion my hve greter potentil to ffect the behvior of Americns, who underestimte the dnger of insulin resistnce nd often overestimte the effect of totl cholesterol or LDL-c on their crdiovsculr helth. In one study, group of New Englnders thought tht cholesterol levels (ie, totl cholesterol or LDL-c) were more importnt to crdiovsculr helth thn blood pressure, smoking, or exercise. 28 In nother study, more people in underserved, rurl Pennsylvni identified high cholesterol s risk fctor thn identified smoking or dibetes. 29 Our results showed tht being insulin resistnt (s suggested by high triglyceride/hdl-c rtio) nd hving LDL-c 142 mg/dl conferred higher risk of CVD thn being insulin sensitive nd hving n elevted LDL-c. The Permnente Journl/ Fll 2015/ Volume 19 No. 4 7

5 Study of the Use of Lipid Pnels s Mrker of Insulin Resistnce to Determine Crdiovsculr Risk The sme ws true for the tretment of being insulin resistnt high LDL-c/HDL-c nd hving n LDL-c/ rtio depends on HDL-c rtio 2.69, its exct problem totl cholesterol/hdl-c whether the LDL-c rtio 4.30, or nonis too high or the HDL-c concentrtion HDL-c is too low. 173 mg/dl. These results In contrst, the suggest tht LDL-c is not triglyceride/hdl-c dominnt predictor of crdiovsculr outcomes rtio is reltively in this study. Consistent specific to insulin with these results, the resistnce. Cox proportionl hzrd model identified insulin resistnce, hypertension, nd mle sex s the risk fctors most importnt in predicting crdiovsculr outcomes in our cohort. An increse in LDL-c of 60 mg/dl conferred only 14% more risk of ischemic hert disese. Similr to our study, the Copenhgen Mle Study sorted pproximtely 3000 Dnish men into 3 groups bsed on triglycerides nd HDL-c levels nd found tht high triglycerides nd low HDL-c were more predictive of subsequent ischemic hert disese thn LDL-c. 21 However, the results of our χ 2 nlyses were even stronger thn those from the Copenhgen Mle Study, likely becuse our popultion hs more people from ethnic groups more likely to be insulin resistnt thn the Dnish popultion. Other studies hve lso shown tht the triglyceride/hdl-c rtio is more predictive thn the LDL-c level, including the Metbolic Syndrome in Active Subjects in Spin study, 23 the Boston Are Helth Study, 24 the Women s Ischemi Syndrome Evlution, 22 nd the study by Bmpi et l. 10 Tble 3. Incidence of ischemic hert disese within 8 yers of the index lipid pnel strtified by insulin resistnce nd by vrious components of the lipid pnel or hypertension Prmeter Insulin sensitive (n = 14,411), % Indeterminte insulin sensitivity (n = 52,515), % Insulin resistnt (n = 13,402), % p vlue Totl cholesterol/hdl-c < > Non-HDL-c 173 mg/dl b < c > 173 mg/dl Blood pressure Normotensive d Hypertensive Fisher exct test p vlue compres 9.3 with b To convert milligrms of cholesterol per deciliter to SI units, multiply by c Fisher exct test p vlue compres 10.3 with d Fisher exct test p vlue compres 14.7 with HDL-c = high-density lipoprotein cholesterol. Tble 4. Hzrd rtios for risk fctors predicting ischemic hert disese t 8 yers fter the index lipid pnel Prmeter Hzrd rtio 95% CI p vlue Insulin resistnce (compred < with insulin sensitivity) LDL-c (> 160 mg/dl compred < with 100 mg/dl) Age, yers < Mle sex < Hypertension < To convert milligrms of cholesterol per deciliter to SI units, multiply by CI = confidence intervl; LDL-c = low-density lipoprotein cholesterol. Dt from lrger trils re lso consistent with our findings. The Helsinki Hert Study showed tht LDL-c ws poor predictor of myocrdil risk, but tht triglycerides nd HDL-c were good predictors. 30 Using the Frminghm risk lgorithm to evlute people with the metbolic syndrome, Wong et l 31 clculted the percentge of CVD tht would be prevented if the LDL-c or the HDL-c could be optimized. They found tht HDL-c ws more powerful risk fctor mong ptients with the metbolic syndrome thn LDL-c nd tht n optiml HDL-c would prevent more events thn n optiml LDL-c. 31 The Physicins Helth Study found tht both HDL-c nd the totl cholesterol/hdl-c rtio were effective predictors of myocrdil infrction but tht potentil surrogte for LDL-c, polipoprotein B-100, ws not. 32 Dt from the Frminghm Study nd the Coronry Primry Prevention Tril showed tht the rtios of cholesterols (totl/hdl-c nd LDL-c/HDL-c) were superior to LDL-c for prediction, but the study did not test the predictiveness of the triglycerides or HDL-c lone. 33 In the Prospective Study of Prvsttin in the Elderly t Risk tril, LDL-c ws not predictive of CVD nd stroke, but HDL-c, LDL-c/HDL-c, nd totl cholesterol/hdl-c were. 34 Other smller studies lso prtilly support our findings. A study evluted the first 100 nondibetic ptients who presented for coronry ngiogrphy t the time of their first hert ttck nd who hd never received tretment tht might hve ffected the evolution of coronry rtery disese. The HDL-c ws significntly predictive of coronry rtery disese, wheres the LDL-c, triglycerides, nd totl cholesterol were not. 35 A cse-control study of 180 Tiwnese hospitlized ptients showed the HDL-c ws more ssocited with coronry rtery stenosis thn the LDL-c. 36 A study of 900 dibetic ptients in Jpnese clinic tht used ultrsound of the crotid rtery to ssess therosclerosis showed tht LDL-c, totl cholesterol, nd triglycerides were not significntly predictive; however, HDL-c, LDL-c/HDL-c, totl 8 The Permnente Journl/ Fll 2015/ Volume 19 No. 4

6 Study of the Use of Lipid Pnels s Mrker of Insulin Resistnce to Determine Crdiovsculr Risk cholesterol/hdl-c, nd non-hdl-c were predictive. 37 Our findings might contrdict the previling wisdom tht LDL-c is powerful risk fctor for ischemic hert disese. There re severl possible explntions for these dt. First, LDL-c >142 mg/dl my not be dngerous enough to sttisticlly demonstrte excessive ischemic disese. The Copenhgen Mle Study used cutoff for high LDL-c of 170 mg/dl 21 ; in contrst, 66% of the KPNC popultion with high LDL-c hd LDL-c vlues < 171 mg/dl. Nonetheless, the Copenhgen Mle Study found tht the triglycerides/ HDL-c rtio ws more predictive thn even these higher levels of LDL-c. Second, the index lipid pnel in this study ws cquired in the bsence of sttin use. However, our results could be explined if most people in the cohort strted using sttins immeditely fter the index mesurement. This could hve mitigted the deleterious effects of elevted LDL-c, thereby nullifying the negtive predictive vlue of the initilly untreted LDL-c. These results would support the continued clinicl evlution of LDL-c to ssess whether sttin should be dministered. However, the results would then suggest tht clinicins should lso focus on insulin resistnce becuse it remins powerful risk fctor even fter tretment of high LDL-c. Alterntively, KPNC my hve wited until fter pproximtely the erly 2000s (until fter the mjority of the big sttin trils were relesed) before rmping up sttin prescriptions for primry prevention. Thus, this cohort my not hve been on sttins long enough for the drugs to reduce ischemic outcomes substntilly. Approximtely hlf the dignoses of ischemic hert disese occurred within the first yer fter the index lipid pnel. If KPNC did not strt ggressively treting LDL with sttins until lte in the decde, then pproximtely hlf the events would hve occurred in the bsence of sttin tretment. If so, our results would indicte tht n untreted LDL-c is not s dngerous s insulin resistnce. In fct, Yeh et l 38 hve lredy published the rte of sttin use in the KPNC members more thn 30 yers of ge who developed their first myocrdil infrction between 1999 nd Sttin use ws strting to rmp up in 2000 but did not rech pek penetrtion until More investigtions re currently in progress to determine the role of sttins in this cohort. By better understnding the risks conferred by the vrious components of the lipid pnel, physicins nd ptients cn do more to mitigte those risks. In ddition to the triglyceride/ HDL-c rtio, the LDL-c/HDL-c nd the totl cholesterol/hdl-c rtio re very predictive of CVD risk. 30,33,39,40 Mny clinicins like the LDL-c/HDL-c rtio becuse the results generlly rnge from 2 to 10, numbers tht re esy to remember. However, the tretment of high LDL-c/HDL-c rtio depends on its exct problem whether the LDL-c is too high or the HDL-c is too low. In contrst, the triglyceride/hdl-c rtio is reltively specific to insulin resistnce. This study would hve confirmed tht high triglyceride/hdl-c rtio is good surrogte for insulin resistnce if other metrics of insulin resistnce hd been mesured lso. Hypertension ws mesured nd ws virtully s strong risk fctor for CVD outcomes s the high triglyceride/hdl-c rtio. Body mss index, weight, ctul blood pressures, blood sugrs, nd hemoglobin A 1c would lso hve been relevnt to this study. Unfortuntely, the ccurcy of the body mss index nd weight dt in 2000 needs clrifiction. The other metrics were beyond the scope of this study. CONCLUSION Physicin counseling cn chnge ptients behviors if effective techniques re used. 41,42 If more physicins understood tht insulin resistnce is huge risk fctor for ischemic hert disese, we could potentilly do more to motivte our ptients. More thn two-thirds of Americns re overweight or obese, 43 nd lrge frction of these hve insulin resistnce. 44 Currently, we my be missing opportunities, becuse sizble frction of ptients don t recll hering their physicins ddress their obesity. 45 Focusing on LDL-c levels is not sufficient; triglycerides nd HDL-c should lso be routinely monitored nd problemtic vlues ddressed to decrese the ssocited risks. v Disclosure Sttement The uthor(s) hve no potentil conflicts to disclose. The Kiser Permnente Northern Cliforni Community Benefit Grnt Progrm funded the study. The progrm hd no role in the cquisition, nlysis, or writing of this study. Acknowledgments We thnk Dvid E Lee, Kiser Foundtion Hospitl, for help interpreting Interntionl Sttisticl Clssifiction of Diseses, Ninth Revision, codes nd George F Bertsch, PhD, University of Wshington, for computtionl help. Nomi L Ruff of RuffDrft Communictions edited previous drft of the mnuscript, for which she received pyment from Kiser Permnente. This study ws supported by grnt from the Kiser Permnente Northern Cliforni Community Benefit Progrm. Mry Corrdo, ELS, provided editoril ssistnce. References 1. Pignone M. Tretment of lipids (including hypercholesterolemi) in primry prevention [Internet]. Wlthm, MA: UpToDte; 2012 Apr 10 [updted 2014 My 2; cited 2015 Apr 29]. Avilble from: com/contents/tretment-of-lipids-includinghypercholesterolemi-in-primry-prevention. 2. The stte of helth cre qulity: reform, the qulity gend nd resource use [Internet]. Wshington, DC: Ntionl Committee for Qulity Assurnce; 2010 [cited 2012 Dec 23]. Avilble from: www. ncq.org/portls/0/stte%20of%20helth%20 Cre/2010/SOHC%202010%20-%20Full2.pdf. 3. HEDIS 2014 technicl specifictions for physicin mesurement: summry tble of mesure chnges [Internet]. Wshington, DC: Ntionl Committee for Qulity Assurnce; 2014 [cited 2015 Jn 30]. Avilble from: DISQM/HEDIS2014/HEDIS_2014%20_List_of_ Physicin_Mesures.pdf. 4. 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