Association Between Triglycerides and Residual Cardiovascular Risk in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease (From the Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D] Trial)

Abstract

Triglyceride (TG) levels encompass several lipoproteins that have been implicated in atherogenic pathways. Whether TG levels independently associate with cardiovascular disease both overall and, in particular among patients with established coronary artery disease (CAD) and type 2 diabetes (T2DM), remains controversial. Data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial was used to evaluate patients with T2DM and CAD. Cox proportional hazards models were used to determine the association between TG levels and outcomes. Stepwise adjustment was performed for demographics, clinical factors, lipid profile and statin treatment. The primary composite outcome was time to CV death, myocardial infarction (MI), or stroke and secondary outcome was CV death. Among 2,307 patients with T2DM and CAD, the mean (±SD) TG levels were 181 (±136) with a median (Q1–Q3) 148mg/dL (104–219). Overall, 51% of patients had TG <150 mg/dL, 18% 150–199 mg/dL, 28% 200–499 mg/dL and 3% ≥500 mg/dL. Participants with elevated TG levels (≥150 mg/dL) were younger (61 vs 63 years, p <0.001), had higher BMI (32 vs 30 kg/m2, p <0.001), more likely to have had prior MI (34.2 vs 30.1%, p = 0.033) and revascularization (25.8 vs 21.4%, p = 0.013), had lower HDL-C (34 vs 39 mg/dL, p <0.001) and higher HbA1c (8 vs 7%, p <0.001). In unadjusted analyses, baseline TG levels were linearly associated with both the primary composite and secondary outcomes. In fully adjusted analyses, every 50 mg/dL increase in TG level was associated with a 3.8% (HR 1.038, 95%CI 1.004–1.072, p <0.001) increase in the primary composite outcome and a 6.4% (HR 1.064 95%CI 1.018–1.113, p <0.001) increase in the secondary outcome. There was no interaction between TG and outcomes within key subgroups including female sex, additional non-coronary atherosclerotic disease, CKD or low LDL (<100 mg/dL). In conclusion, among patients with T2DM and CAD, elevated TG were independently associated with adverse cardiovascular outcomes, even after adjustment for clinical and simple biochemical covariates. Triglyceride (TG) levels encompass several lipoproteins that have been implicated in atherogenic pathways. Whether TG levels independently associate with cardiovascular disease both overall and, in particular among patients with established coronary artery disease (CAD) and type 2 diabetes (T2DM), remains controversial. Data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial was used to evaluate patients with T2DM and CAD. Cox proportional hazards models were used to determine the association between TG levels and outcomes. Stepwise adjustment was performed for demographics, clinical factors, lipid profile and statin treatment. The primary composite outcome was time to CV death, myocardial infarction (MI), or stroke and secondary outcome was CV death. Among 2,307 patients with T2DM and CAD, the mean (±SD) TG levels were 181 (±136) with a median (Q1–Q3) 148mg/dL (104–219). Overall, 51% of patients had TG <150 mg/dL, 18% 150–199 mg/dL, 28% 200–499 mg/dL and 3% ≥500 mg/dL. Participants with elevated TG levels (≥150 mg/dL) were younger (61 vs 63 years, p <0.001), had higher BMI (32 vs 30 kg/m2, p <0.001), more likely to have had prior MI (34.2 vs 30.1%, p = 0.033) and revascularization (25.8 vs 21.4%, p = 0.013), had lower HDL-C (34 vs 39 mg/dL, p <0.001) and higher HbA1c (8 vs 7%, p <0.001). In unadjusted analyses, baseline TG levels were linearly associated with both the primary composite and secondary outcomes. In fully adjusted analyses, every 50 mg/dL increase in TG level was associated with a 3.8% (HR 1.038, 95%CI 1.004–1.072, p <0.001) increase in the primary composite outcome and a 6.4% (HR 1.064 95%CI 1.018–1.113, p <0.001) increase in the secondary outcome. There was no interaction between TG and outcomes within key subgroups including female sex, additional non-coronary atherosclerotic disease, CKD or low LDL (<100 mg/dL). In conclusion, among patients with T2DM and CAD, elevated TG were independently associated with adverse cardiovascular outcomes, even after adjustment for clinical and simple biochemical covariates. Patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are at high risk for future cardiovascular (CV) events. Among other factors, hypertriglyceridemia has been implicated as a potential contributor to the observed residual risk in patients with T2DM despite statin therapy. Mechanistically, triglycerides (TG), and more specifically triglyceride-rich lipoprotein remnants, have links with a proatherosclerotic milieu through their ability to, (1) enter the subendothelial vascular space and promote atherogenesis,1Mamo JC Proctor SD Smith D Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma.Atherosclerosis. 1998; 141: S63-S69Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar,2Zilversmit DB A proposal linking atherogenesis to the interaction of endothelial lipoprotein lipase with triglyceride-rich lipoproteins.Circ Res. 1973; 33: 633-638Crossref PubMed Scopus (244) Google Scholar (2) impair the anti-atherogenic efficiency of high-density lipoprotein (HDL) reverse cholesterol transport3Skeggs JW Morton RE LDL and HDL enriched in triglyceride promote abnormal cholesterol transport.J Lipid Res. 2002; 43: 1264-1274Crossref PubMed Google Scholar and (3) increase the susceptibility for low-density lipoprotein to become oxidized.4Steinberg D Parthasarathy S Carew TE Khoo JC Witztum JL Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.N Engl J Med. 1989; 320: 915-924Crossref PubMed Google Scholar Hypertriglyceridemia has been shown to generally associate with increased risk of incident cardiovascular disease,5Bansal S Buring JE Rifai N Mora S Sacks FM Ridker PM Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women.JAMA. 2007; 298: 309-316Crossref PubMed Scopus (1234) Google Scholar, 6Hokanson JE Austin MA Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.J Cardiovasc Risk. 1996; 3: 213-219Crossref PubMed Google Scholar, 7Nordestgaard BG Varbo A Triglycerides and cardiovascular disease.Lancet. 2014; 384: 626-635Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar, 8Sarwar N Danesh J Eiriksdottir G Sigurdsson G Wareham N Bingham S Boekholdt SM Khaw KT Gudnason V Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies.Circulation. 2007; 115: 450-458Crossref PubMed Scopus (1103) Google Scholar however whether a similar relationship holds for patients with established CAD is less clear. Specifically, whether elevated TG levels are independently associated with CV events or simply serve as a marker for other risk factors is controversial.9Emerging Risk Factors C Di Angelantonio E Sarwar N Perry P Kaptoge S Ray KK Thompson A Wood AM Lewington S Sattar N Packard CJ Collins R Thompson SG Danesh J Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (1964) Google Scholar While post hoc analyses of trials have shown elevated TG levels to confer increased risk for CV events in patients with established CAD,10Faergeman O Holme I Fayyad R Bhatia S Grundy SM Kastelein JJ LaRosa JC Larsen ML Lindahl C Olsson AG Tikkanen MJ Waters DD Pedersen TR Steering Committees of ITrials TNTPlasma triglycerides and cardiovascular events in the treating to new targets and incremental decrease in end-points through aggressive lipid lowering trials of statins in patients with coronary artery disease.Am J Cardiol. 2009; 104: 459-463Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 11Miller M Cannon CP Murphy SA Qin J Ray KK Braunwald E Investigators PI-T Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial.J Am Coll Cardiol. 2008; 51: 724-730Crossref PubMed Scopus (487) Google Scholar, 12Schwartz GG Abt M Bao W DeMicco D Kallend D Miller M Mundl H Olsson AG Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins.J Am Coll Cardiol. 2015; 65: 2267-2275Crossref PubMed Scopus (173) Google Scholar these studies have either relegated T2DM to a binary variable in subgroup analysis, or been performed in a pre-statin era. Using data from BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes), the aims of this study were to; (1) determine the prevalence and distribution of hypertriglyceridemia; (2) examine the association between baseline TG levels and CV events overall and; (3) evaluate these relationships in key subgroups with either disparate or residual risk. The design13Brooks MM Frye RL Genuth S Detre KM Nesto R Sobel BE Kelsey SF Orchard TJ Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial IHypotheses, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial.Am J Cardiol. 2006; 97: 9G-19GAbstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar and primary outcome results14Group BDS Frye RL August P Brooks MM Hardison RM Kelsey SF MacGregor JM Orchard TJ Chaitman BR Genuth SM Goldberg SH Hlatky MA Jones TL Molitch ME Nesto RW Sako EY Sobel BE A randomized trial of therapies for type 2 diabetes and coronary artery disease.N Engl J Med. 2009; 360: 2503-2515Crossref PubMed Scopus (1538) Google Scholar of the BARI 2D trial have been previously published. In brief, BARI-2D was an international, multicenter trial which enrolled 2,368 participants with T2DM and angiographically documented stable ischemic heart disease between January 2001 and March 2005. Participants were randomized using a 2 × 2 factorial design; one level dictating cardiovascular treatment, the other dictating T2DM treatment. The randomized cardiac treatment strategies included intensive medical therapy with prompt revascularization (within 4 weeks) or intensive medical therapy with revascularization only when clinically indicated. The randomized glycemic control strategies compared primarily insulin-sensitizing (i.e., thiazolidinediones and/or metformin) versus primarily insulin-providing (i.e. insulin and/or sulphonylurea). The results of the primary analysis showed no significant benefit of prompt revascularization over initial medical therapy, nor was there any notable difference in outcomes between the glycemic strategies. Beyond the investigational components, the protocol included guideline-mandated concomitant risk factor control for hypertension, dyslipidemia and obesity, in addition to a goal HbA1c of <7.0% regardless of randomization assignment. Major exclusion criteria included definite need for prompt invasive intervention as determined by the treating cardiologist, prior coronary revascularization within the past 12 months, class III or IV congestive heart failure, creatinine >2.0 mg/dL, TG >1000 mg/dL or HbA1c >13%. Institutional review boards at each participating site approved the protocol and all patients provided written informed consent. The BARI 2D trial data were obtained on request from the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung, and Blood Institute under a data use agreement. The protocol for this analysis was approved by the Duke University Institutional Review Board. Data from participants in the BARI-2D trial with baseline fasting lipids were considered for this analysis. As per trial protocol, lipid measures were obtained from fasting blood acquired prior to randomization, frozen locally and measured at the core laboratory. HDL-C was quantified using standard enzymatic techniques after the removal of Apolipoprotein-B (Apo-B) containing particles; total cholesterol and TG were quantified with direct enzymatic techniques, and LDL-C was determined through the Friedewald equation. Systolic and diastolic BP were obtained in the seated position using an appropriately sized cuff following 5 minutes of rest; the mean of three BP readings was used and reported to the nearest 2mmHg. The primary endpoint of this analysis mirrored that of the primary trial, namely a composite of time to CV death, myocardial infarction (MI) or stroke. The secondary outcomes were the individual components of the primary endpoint in addition to coronary revascularization and all-cause death. The diagnosis of spontaneous myocardial infarction was based on a doubling of cardiac biomarkers (creatine kinase-MB or troponin) and evidence of ischemia on the basis of symptoms, electrocardiography, or imaging. infarction was by a core stroke and of were by an independent clinical events The was for and for other outcomes. Participants were by baseline TG was performed by the at a TG of which is as in SM C KK S J Goldberg R Hlatky MA Jones D N JJ Smith J on the of blood a of the of on clinical Am Coll Cardiol. PubMed Scopus Google Scholar Participants in the mg/dL were (1) 150–199 mg/dL, (2) 200–499 mg/dL, (3) mg/dL. are as mean (±SD) or median are as between elevated and TG was performed using the or were compared using or the association between TG levels and clinical outcomes, Cox proportional hazards models were In to determine and which factors any a of models were with of as 2 sex, and BP and 4 T2DM 5 LDL-C and statin As the Friedewald LDL-C in the of elevated a analysis was performed by 5 after LDL-C in patients with TG MJ Jones of a vs the Friedewald for low-density lipoprotein cholesterol levels from the standard lipid PubMed Scopus Google Scholar use the for all was performed to data with no and 2 included with models the data the and were over the data The was for using and the proportional hazards for all using were as a post hoc analysis, adjusted for a of total atherogenic including as as their and and TG are to was and using interaction analyses were performed for the composite and CV using the data Cox models were with the of and their The following with were sex, T2DM years, as time from diagnosis to trial CKD or by non-coronary vascular disease including arterial disease and/or disease low LDL and statin are per 50 mg/dL increase in TG by the interaction with T2DM are per 50 mg/dL increase in TG at the following and The study of 2,307 patients of the overall study with fasting TG levels at the baseline overall and by baseline TG to the overall trial, the median of the study was with the and of of the had with an overall median T2DM of under The were on a Triglyceride levels were with a mean of 181 (±136) and a median of mg/dL (104–219). Overall, 51% of patients had TG <150 mg/dL, 18% 150–199 mg/dL, 28% and 3% of of of and/or BP BP at or = = BMI = = = heart = HbA1c = HDL-C = high-density lipoprotein MI = myocardial LDL-C = low-density lipoprotein = ischemic in a new = = BMI = = = heart = HbA1c = HDL-C = high-density lipoprotein MI = myocardial LDL-C = low-density lipoprotein = ischemic with with levels mg/dL, patients with TG levels at or mg/dL were younger and more likely to of were similar between the as was with elevated TG were more likely to have a of MI or the of heart failure, prior stroke and non-coronary vascular disease were similar between the in T2DM insulin and were observed between however these were and clinically Patients with elevated TG had higher overall total cholesterol and were more likely to have lower profile was similar with the of higher of and use in patients with elevated TG The of patients with elevated TG are by in In relationships were generally observed with the TG level more likely to have lower HDL-C cholesterol and higher insulin levels insulin in the on however with TG levels were likely to on TG levels were linearly associated with the primary composite outcome of CV death, MI and stroke In the unadjusted every 50 mg/dL increase in TG level was associated with a (HR 95%CI increase in CV and a (HR 95%CI increase in CV death. between baseline TG level and both primary and secondary outcomes are in In of sex, BP and in the increased the of TG levels on risk for adverse CV outcomes. In the addition of T2DM LDL-C and statin use all the of TG levels on risk for both outcomes. TG levels in each In the fully adjusted each increase in TG was associated with a 3.8% (HR 1.038, 95%CI increase in the risk of CV and a 6.4% (HR 95%CI increase in the risk of CV death. A analysis using adjusted LDL-C levels for patients with TG mg/dL of these relationships In an analysis, baseline was with TG levels = p for LDL-C in the fully adjusted TG levels were no of the composite (HR 95%CI p = of CV (HR p = between TG levels and key were for the primary composite endpoint and CV death. As in there were no significant for either of the between TG levels and of sex, T2DM non-coronary atherosclerotic disease, LDL-C mg/dL or statin and secondary outcomes, to 50 mg/dL increase in TG of Diabetes LDL-C LDL-C of Diabetes LDL-C LDL-C = LDL-C = low-density lipoprotein low LDL and the was using data were using the data and the that were used in the Cox in a new CKD = LDL-C = low-density lipoprotein cholesterol. low LDL and the was using data were using the data and the that were used in the Cox performed in a of patients with T2DM and established CAD, has several notable a of patients with T2DM and CAD had elevated baseline fasting triglyceride levels were linearly associated with cardiovascular events. the relationship between baseline TG levels and cardiovascular events significant despite adjustment for clinical and biochemical covariates. the relationship was in subgroups including with low The of a relationship between TG levels and CV events in a of patients with T2DM and established CAD prior studies that have In a of with T2DM from of have CAD, the of TG levels was independently associated with all-cause after adjustment for other lipid MA A G Plasma triglycerides predict all-cause in with type 2 diabetes a 2014; PubMed Scopus Google Scholar by were reported from a analysis of patients in an which included patients with either T2DM and/or CAD C M D A S triglycerides are associated with increased cardiovascular medical and a analysis of patients with high residual cardiovascular Am PubMed Scopus Google Scholar In the study by with TG mg/dL were at higher risk of stroke or revascularization when compared with a with TG <150 mg/dL. In studies of patients with a baseline TG levels in both the and trials were associated with both weeks) and cardiovascular events death, GG Abt M Bao W DeMicco D Kallend D Miller M Mundl H Olsson AG Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins.J Am Coll Cardiol. 2015; 65: 2267-2275Crossref PubMed Scopus (173) Google Scholar an analysis of the 22 trial which enrolled showed lower TG levels mg/dL) to independently associated with a risk of CV events and recurrent M Cannon CP Murphy SA Qin J Ray KK Braunwald E Investigators PI-T Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial.J Am Coll Cardiol. 2008; 51: 724-730Crossref PubMed Scopus (487) Google Scholar study this prior in several was a of a of patients with both T2DM and angiographically a relegated to subgroup in prior the studies results high trial data which included and outcome events. factors are likely to have increased in the of a relationship and to analysis TG levels to associated with future risk of cardiovascular events in patients with established CAD despite low levels of LDL-C mg/dL). is with prior on the S S residual cardiovascular risk in patients with diabetes and high versus triglycerides despite LDL PubMed Scopus Google Scholar and TG levels as an of residual risk observed in patients with T2DM to recurrent events despite low LDL-C as as of patients a similar lipid on statin therapy, there a with treatment W S C Hypertriglyceridemia in the National and Full Text Full Text PDF PubMed Scopus Google Scholar, H S and of dyslipidemia and lipid levels in with and cardiovascular the National and 2008; PubMed Scopus Google Scholar, dyslipidemia and risk of coronary heart disease in with diabetes mellitus and low-density lipoprotein cholesterol J Cardiol. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar with other ML SD between triglyceride lowering and of cardiovascular risk a review and analysis of randomized PubMed Scopus Google C Risk Factors C Sarwar N Di Angelantonio E Boekholdt SM W H D D Danesh J and coronary disease: analysis of Full Text Full Text PDF PubMed Scopus Google Scholar results that TG levels are associated with increased risk for CV events in patients with established however whether triglycerides are in the or simply a marker of risk remains analysis that even after for factors associated with both TG levels and CV risk as T2DM and triglyceride levels associated with CV events. A randomization study that the risk through either LDL-C or TG lowering was to the proportional in Kastelein Ray KK MJ Packard CJ C Wood AM Di Angelantonio E Danesh J of and with risk of coronary heart disease.JAMA. PubMed Scopus Google Scholar which the primary of the While adjustment for have to a relationship between triglyceride levels and this was measured in performed an adjustment for which is considered a marker for (i.e., and showed a of the association between outcomes and TG is likely a of both the between TG levels and as as the potential for independent of TG levels and LDL-C to measured in clinical of independent in CV risk to in TG levels clinically The and independent relationship with risk that TG levels by any associated with cardiovascular the of in clinical trials including statins and have been in their ability to lower CV risk to (1) in TG levels or (2) the of to a which to from observed triglyceride In to prior the of with Trial study of a of in cardiovascular events in patients with elevated TG the were independent of TG level Miller M C JC Investigators risk with for Engl J Med. PubMed Scopus Google Scholar that high blood levels of from were associated with the CV observed in as compared to lipid or lipoprotein biomarkers as TG Miller M C JC C levels predict cardiovascular benefit in of Scholar to the relationship between TG levels and CV outcomes is the that the trial to Risk in CV Risk has been to While there are in the in and in their data similar in levels of of are with more and TG level lowering a has been shown to TG levels by and increase HDL-C by and is in a III trial to in P M H S W BG JC P Ridker PM and of the to cardiovascular outcomes by triglycerides in patients with diabetes PubMed Scopus Google Scholar In for and have trials with in TG of and results in in triglycerides and LDL-C in C results in and in Scholar Whether these TG confer benefit independent of their on remains to study is a post hoc analysis of a clinical trial and in The of residual and reverse data potential clinical as use and The was and and of the results to a of patients with T2DM and CAD. BARI 2D patients with hypertriglyceridemia and included only a the to which the relationship at high TG levels from In conclusion, this study of patients with T2DM and CAD from the BARI 2D trial, baseline triglyceride levels were independently associated with adverse cardiovascular outcomes. Whether lowering TG levels to cardiovascular outcomes remains to from Diabetes and the of from and the of the additional to from and the of the study of the and from and of the of of and from and from of study as as and from and of the from and both have to Data and analysis, and analysis, and and and and and with

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