Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial
Authors: Roberto S. Kalil, Jeffrey H. Wang, Ian H. de Boer, Roy O. Mathew, Joachim H. Ix, Arif Asif, Xuefeng Shi, William E. Boden
Journal: Kidney International (2015)

Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, and prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin in patients with established coronary heart disease. Here we conducted a post hoc analysis of the AIM-HIGH trial examining whether participants derived cardiovascular or renal benefits when stratified by renal function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among the CKD subset, demographics and cardiovascular disease (CVD) risk factors were well balanced in the ERN and placebo arms. Compared with placebo, CKD participants receiving ERN had a significant decrease in triglycerides by a median of 59.0 mg/dl, and high-density lipoprotein cholesterol significantly increased by a mean of 11.3 mg/dl over a mean follow-up of 3 years. CVD events were similar between CKD participants in both arms. However, all-cause mortality was significantly higher in the ERN group (hazard ratio of 1.73). Mean change in eGFR among ERN-treated CKD participants was not significantly different between study arms. Thus, among AIM-HIGH participants with CKD, the addition of ERN to simvastatin for secondary prevention of CVD improved triglyceride and high-density lipoprotein-cholesterol concentrations but did not improve cardiovascular outcomes or kidney function, and was associated with higher all-cause mortality. Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, and prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin in patients with established coronary heart disease. Here we conducted a post hoc analysis of the AIM-HIGH trial examining whether participants derived cardiovascular or renal benefits when stratified by renal function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among the CKD subset, demographics and cardiovascular disease (CVD) risk factors were well balanced in the ERN and placebo arms. Compared with placebo, CKD participants receiving ERN had a significant decrease in triglycerides by a median of 59.0 mg/dl, and high-density lipoprotein cholesterol significantly increased by a mean of 11.3 mg/dl over a mean follow-up of 3 years. CVD events were similar between CKD participants in both arms. However, all-cause mortality was significantly higher in the ERN group (hazard ratio of 1.73). Mean change in eGFR among ERN-treated CKD participants was not significantly different between study arms. Thus, among AIM-HIGH participants with CKD, the addition of ERN to simvastatin for secondary prevention of CVD improved triglyceride and high-density lipoprotein-cholesterol concentrations but did not improve cardiovascular outcomes or kidney function, and was associated with higher all-cause mortality. Coronary heart disease is a leading cause of morbidity and mortality in chronic kidney disease (CKD). Individuals with CKD are at a greater risk for major adverse cardiac events than the general population.1Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9021) Google Scholar Despite this, traditional risk factor reduction strategies that reduce major adverse cardiac event in the general population, such as low-density lipoprotein cholesterol (LDL-C) lowering, confer less benefit in CKD patients.2Cholesterol Treatment Trialists’ (CTT) CollaborationEfficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials.Lancet. 2010; 376 (168): 1670Abstract Full Text Full Text PDF PubMed Scopus (4550) Google Scholar In the Study of Heart and Renal Protection, although treatment with simvastatin plus ezetimibe in subjects with CKD led to a 17% reduction in a composite cardiovascular outcome compared with placebo, it did not reduce all-cause or coronary heart disease mortality.3Biagent C. Landray M.J. Reith C. et al.The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial.Lancet. 2011; 377: 2181-2192Abstract Full Text Full Text PDF PubMed Scopus (1892) Google Scholar Low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels are both associated with CKD.4Vaziri N.D. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences.Am J Physiol. 2006; 290: F262-f272Crossref PubMed Scopus (392) Google Scholar Niacin raises HDL-C and lowers TG levels. However, it is not known whether raising HDL-C and lowering TG translates into improved cardiac outcomes in CKD patients. Prior studies suggest that lipid-lowering therapy may also prevent progression of CKD.5Shepherd J. Kastelein J. Bittner V. et al.Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary artery disease: The Treating to New Targets (TN) study.Clin J Am Soc Nephrol. 2007; 2: 1131-1139Crossref PubMed Scopus (278) Google Scholar Although animal studies suggest that niacin may protect against GFR loss,6Cho K. Kim H. Rodriguez-Iturbe B. et al.Niac in ameliorates oxidative stress, inflammation, proteinuria, and hypertension in rats with chronic renal failure.Am J Physiol Renal Physiol. 2009; 297: F106-F113Crossref PubMed Scopus (88) Google Scholar to our knowledge, the effect of extended-release niacin (ERN) on longitudinal change in kidney function in humans has not been studied previously. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High TGs: Impact on Global Health Outcomes (AIM-HIGH) tested the hypothesis that ERN, when added to intensive statin therapy, reduced major adverse cardiac event in stable coronary heart disease patients preselected for low baseline HDL-C and elevated TGs as compared with placebo. Ezetimibe could be added to either arm, as needed, to achieve and maintain an on-treatment LDL-C between 40 and 80 mg/dl. The primary outcome study findings from AIM-HIGH did not show incremental clinical benefit of ERN versus placebo on major adverse cardiac event when added to optimal LDL-C reduction therapy despite a significant improvement in the lipid profile.7AIM-HIGH InvestigatorsThe role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial.Am Heart J. 2011; 161: 538-543Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar The present investigation was a post hoc analysis of participants with CKD enrolled in the AIM-HIGH trial. Because the CKD population represents a subset with high cardiac risk, we hypothesized that raising HDL-C and lowering TG with ERN would improve cardiovascular outcomes in these subjects. Secondary objectives were to evaluate the effect of ERN on longitudinal change in kidney function, as well as safety and tolerability in participants with CKD. Baseline characteristics: Of the 3413 participants with non-missing estimated glomerular filtration rate (eGFR) in the AIM-HIGH trial, 85.2% were male, 3.4% were African Americans, and 4.1% were of Hispanic ethnicity. Five hundred and five study participants (14.8%) had CKD at baseline. Among these, the mean eGFR was 50.3±7.7 ml/min per 1.73 m2. In all, 496 participants (98.2%) had an eGFR within the range of 30–59 ml/min per 1.73 m2, and 9 (1.8%) had an eGFR<30 ml/min per 1.73 m2. Approximately 80% of the CKD participants were male, 4% were African Americans, and 3.4% were Hispanics. Compared with participants without CKD, those with CKD were older and more likely to be female, had higher prevalence of diabetes and hypertension, but were less likely to use tobacco. Systolic blood pressures and pulse pressures were slightly higher in CKD participants (Table 1).Table 1Baseline demographics and clinical characteristics among AIM-HIGH participants stratified by CKD StatusCKD (N=505)No CKD (N=2908)P-valueAge (years), mean (s.d.)70.7 (7.3)62.5 (8.4)<0.001Gender (male), N (%)408 (80.8)2501 (86.0)0.002Race—African American, N (%)20 (4.0)97 (3.3)0.476Ethnicity—Hispanic, N (%)19 (3.8)121 (4.2)0.676Current smoker, N (%)58 (11.6)564 (19.5)<0.001Coronary artery disease, N (%)452 (89.5)2694 (92.6)0.015Diabetes, N (%)207 (41.0)951 (32.7)<0.001Hypertension, N (%)401 (79.4)2037 (70.0)<0.001Diastolic BP (mm Hg), mean (s.d.)71.4 (10.2)74.9 (9.6)<0.001Systolic BP (mm Hg), mean (s.d.)130.5 (17.4)127.9 (16.1)<0.001Pulse pressure (mm Hg), mean (s.d.)59.1 (16.4)53.0 (13.4)<0.001Use of ACE-Is or ARBs, N (%)391 (77.4)2137 (73.5)0.062Abbreviations: AIM-HIGH, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; BP, blood pressure; CKD, chronic kidney disease. Open table in a new tab Abbreviations: AIM-HIGH, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; BP, blood pressure; CKD, chronic kidney disease. Among participants with CKD randomized to ERN (n=254) or placebo (n=251), demographic variables, medical conditions, and CAD risk factors were balanced between treatment arms. Lipid profiles in CKD subjects randomized to placebo or ERN were also similar at baseline (Table 2).Table 2Baseline demographic features and clinical characteristics by randomization in AIM-HIGH participants with CKDPlacebo (N=251)Niacin (N=254)P-valueAge (years), mean (s.d.)70.8 (7.4)70.6 (7.2)0.764Gender (male), N (%)200 (79.7)208 (81.9)0.529Race—African American, N (%)10 (4.0)10 (3.9)0.978Ethnicity—Hispanic, N (%)6 (2.4)13 (5.1)0.107Current smoker, N (%)33 (13.3)25 (10.0)0.244Body mass index (kg/m2), mean (s.d.)30.4 (5.8)30.9 (5.4)0.390Coronary artery disease, N (%)231 (92.0)221 (87.0)0.066Diabetes, N (%)102 (40.6)105 (41.3)0.873Metabolic syndrome, N (%)206 (83.1)214 (84.3)0.719Hypertension, N (%)194 (77.3)207 (81.5)0.243LDL cholesterol, mean (s.d.)74.3 (21.2)73.8 (21.9)0.794HDL cholesterol, mean (s.d.)34.5 (6.2)34.9 (6.1)0.462Triglycerides, median (Q1,Q3)160 (133 ,231)175 (132, 222)0.839Diastolic BP (mm Hg), mean (s.d.)70.9 (10.5)71.9 (9.8)0.290Systolic BP (mm Hg), mean (s.d.)130.1 (16.9)130.9 (17.9)0.602Pulse pressure (mm Hg), mean (s.d.)59.2 (16.7)59.0 (16.2)0.920Use of ACE-Is or ARBs, N (%)191 (76.1)200 (78.7)0.453Abbreviations: AIM-HIGH, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; BP, blood pressure; CKD, chronic kidney disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Q1,Q3, interquartile range. Open table in a new tab Abbreviations: AIM-HIGH, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; BP, blood pressure; CKD, chronic kidney disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Q1,Q3, interquartile range. Participants from both CKD and non-CKD groups achieved significant increases in HDL-C and decreases in TG concentrations in the ERN arm relative to placebo. In the CKD group, baseline HDL-C concentration was 34.5 mg/dl and 34.9 mg/dl for the placebo and ERN groups, respectively. At 3 years, mean HDL-C concentrations were 39.2 (8.2) mg/dl and 45.9 (12.6) mg/dl, respectively (placebo vs. ERN, P<0.0001). In the CKD group, median (interquartile range) baseline TG concentration was 160.0 mg/dl (133.0, 231.0 mg/dl) for the placebo group and 175.0 mg/dl (132.0, 222.0 mg/dl) for the ERN group. At 3 years, median TG concentrations were 153.0 mg/dl (111.0, 192.0 mg/dl) and 113.0 mg/dl (80.0, 156.0 mg/dl) for placebo and ERN, respectively (P<0.0001). ERN had a greater effect on TG in the CKD group with a median decrease of 59.0 mg/dl, compared with a median decrease of 47.0 mg/dl in participants without CKD (P=0.031), after 3 years of therapy (Table 3).Table 3Lipid levels by CKD status and treatment: actual values and change from baseline valuesLipid ParameterTimeCKDaCKD: Year 1-N=454; Year 3-N=233.(N=505)No CKDbNo CKD: Year 1-N=2660; Year 3-N=1505.(N=2908)Placebo (N=251)Niacin (N=254)Placebo (N=1444)Niacin (N=1464)Total cholesterol (mg/dl), mean (s.d.)Baseline146.6 (26.0)146.1 (26.3)144.9 (26.7)145.3 (28.5)Year 1144.0 (25.1)137.0 (25.0)143.4 (25.6)138.2 (27.3)Change from baseline-3.1 (27.3)-8.9 (31.0)-1.2 (31.1)-7.0 (32.6)Year 3140.7 (25.9)137.7 (32.1)141.6 (23.4)136.7 (27.6)Change from baseline-8.6 (32.4)-10.6 (36.8)-4.7 (28.9)-10.0 (33.8)LDL cholesterol (mg/dl), mean (s.d.)Baseline74.3 (21.2)73.8 (21.9)73.9 (22.9)74.3 (23.7)Year 170.4 (18.1)65.4 (20.0)70.4 (19.0)66.6 (19.9)Change from baseline-4.8 (21.8)-8.4 (25.6)-3.5 (24.8)-7.9 (26.2)Year 367.9 (21.3)66.2 (24.1)68.4 (19.0)65.0 (21.5)Change from baseline-8.8 (26.8)-9.2 (31.2)-6.6 (24.0)-10.6 (27.8)HDL cholesterol (mg/dl), mean (s.d.)Baseline34.5 (6.2)34.9 (6.1)35.0 (5.5)34.5 (5.6)Year 138.5 (8.4)45.5 (12.2)38.4 (7.5)43.3 (10.6)Change from baseline3.9 (5.9)10.8 (10.1)3.4 (5.5)8.8 (8.2)Year 339.2 (8.2)45.9 (12.6)39.1 (7.6)43.8 (11.1)Change from baseline4.7 (6.3)11.3 (11.3)4.2 (5.7)9.5 (9.0)Lipoprotein (a) (nmol/l), median (Q1, Q3)Baseline33.3 (15.3, 105.7)34.8 (15.3, 112.8)32.3 (12.8, 122.4)36.1 (13.4, 127.6)Year 132.8 (14.8, 112.14)24.6 (8.2, 90.0)30.1 (9.7, 124.9)27.5 (8.4, 110.7)Change from baseline-0.7 (-9.4, 5.8)-5.6 (-19.4, 0.0)-1.3 (-9.4, 3.8)-6.0 (-20.2, 0.1)Triglyceride (mg/dl), median (Q1, Q3)Baseline160.0 (133.0, 231.0)175.0 (132.0, 222.0)163.0 (131.0, 215.0)166.0 (130.5, 218.0)Year 1153.5 (119.0, 213.5)112.0 (79.0, 164.0)155.0 (118.0, 207.0)122.5 (88.0, 172.0)Change from baseline-10.5 (-37.5, 28.5)-55.0 (-93.0, -9.0)-8.0 (-45.0, 30.0)-43.0 (-80.0, -5.0)Year 3153.0 (111.0, 192.0)113.0 (80.0, 156.0)152.0 (115.0, 206.0)121.0 (85.0, 174.0)Change from baseline-20.0 (-60.0, 22.0)-59.0 (-111.0, -16.0)-14.0 (-53.0, 29.0)-47.0 (-90.0, -6.0)Abbreviations: CKD, chronic kidney disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Q1,Q3, interquartile range.a CKD: Year 1-N=454; Year 3-N=233.b No CKD: Year 1-N=2660; Year 3-N=1505. Open table in a new tab Abbreviations: CKD, chronic kidney disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Q1,Q3, interquartile range. There was no clinical benefit of randomization to ERN for the composite cardiovascular disease (CVD) primary end points within the CKD group. Among CKD participants, 60 subjects (23.6%) in the ERN arm and 60 (23.93%) in the placebo arm reached the primary end point (ERN vs. placebo hazard ratio 1.02, 95% confidence interval 0.71, 1.45). All-cause mortality was higher for the ERN group with 39 deaths (15.4%) compared with 23 deaths (8.9%) in the placebo group (ERN vs. placebo hazard ratio=1.73, 95% confidence interval 1.03, 2.89, P=0.038). However, there was no significant difference in cardiovascular mortality in the CKD group assigned to ERN with 19 CV deaths (7.5%) compared with 12 CV deaths (4.8%) in the placebo group (ERN vs. placebo hazard ratio=1.62, 95% confidence interval 0.78, 3.33). We did not observe interaction between ERN, kidney function, and cardiovascular end points in models with/without eGFR stratification (data not shown). Most of the noncardiovascular deaths were due to cancer (Table 4).Table 4Cardiovascular end-point events and hazard ratios in ERN versus placebo treated stratified by baseline CKD statusClinical eventCKDNo CKDPlacebo (N=251)Niacin (N=254)Niacin vs. Placebo HRaHazard ratios are based on model with baseline eGFR group. (95% CI)Placebo (N=1444)Niacin (N=1464)Niacin vs. Placebo HR (95% CI)Exposure (patient-year)74873744444477Primary end pointbPrimary end point is defined as the first occurrence of CHD death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.60 (23.9%)60 (23.6%)1.02 (0.71–1.45)214 (14.9%)222 (15.2%)1.03 (0.85–1.24)Secondary end points First occurrence of CHD death, nonfatal MI, ischemic stroke, or “high risk” acute coronary syndrome40 (15.9%)41 (16.1%)1.05 (0.68–1.63)118 (8.2%)130 (8.9%)1.10 (0.85–1.41) First occurrence of CHD death, nonfatal MI, or ischemic stroke35 (13.9%)39 (15.4%)1.15 (0.73–1.82)103 (7.1%)117 (8.0%)1.13 (0.87–1.47) Cardiovascular mortality12 (4.8%)19 (7.5%)1.62 (0.78–3.33)26 (1.8%)26 (1.8%)0.99 (0.57–1.70)Overall mortality23 (9.2%)39 (15.4%)1.73 (1.03–2.89)*P=0.038.59 (4.1%)57 (3.9%)0.96 (0.67–1.38) Cardiac12 (4.8%)16 (6.3%)1.35 (0.64–2.86)22 (1.5%)22 (1.5%)0.99 (0.55–1.79) Vascular, noncardiac0 (0.0%)3 (1.2%)NA4 (0.3%)4 (0.3%)0.99 (0.25–3.97) Noncardiovascular11 (4.4%)18 (7.1%)1.67 (0.79–3.53)32 (2.2%)29 (2.0%)0.90 (0.54–1.49)Cardiovascular death or nonfatal MI30 (12.0%)34 (13.4%)1.16 (0.71–1.90)91 (6.3%)95 (6.5%)1.03 (0.78–1.38)Abbreviations: CHD, coronary heart disease; CKD, chronic kidney disease; ERN, extended-release niacin; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; NA, not applicable.a Hazard ratios are based on model with baseline eGFR group.b Primary end point is defined as the first occurrence of CHD death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.* P=0.038. Open table in a new tab Abbreviations: CHD, coronary heart disease; CKD, chronic kidney disease; ERN, extended-release niacin; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; NA, not applicable. When the entire study sample was evaluated together regardless of CKD status, there was a mean decrease in eGFR of 2.8% (14.0%) in those randomized to placebo (n=872) and a 1.2% (14.8%) decrease in those treated with ERN (n=866) over 3 years (P=0.03). There was statistically significant interaction between treatment and CKD status (P-interaction=0.004) for percent change in eGFR at year 3. Data examining the subset with and without CKD separately are shown in Table 5. In participants with CKD, there was a 3.3% (24.2%) improvement in eGFR from baseline to year 3 in those randomized to placebo, whereas there was a 1.8% (22.3%) decrease in those randomized to ERN, a result that did not reach statistical significance (P=0.10). Conversely, in the subset without CKD, there was a 3.8% (13.6%) decrease in eGFR in those randomized to placebo, whereas those randomized to ERN experienced only a 1.1% (13.5%) decrease in eGFR over 3 years (Figure 1). This finding was statistically significant (P=0.0001). No new incident cases of CKD were observed during the study.Table 5Effect of randomization to ERN versus placebo on change in eGFRTimeCKDNo CKDPlacebo (N=251)Niacin (N=254)P-valuePlacebo (N=1444)Niacin (N=1464)P-valueBaseline eGFR, mean (s.d.)50.5 (7.6)50.0 (7.7)84.9 (12.6)84.4 (12.9)Year 1, N19119310931106Change from baseline in eGFR, mean (s.d.)2.0 (10.3)2.6 (10.1)0.5-1.4 (9.1)0.3 (8.7)<0.0001Percent change from baseline in eGFR, mean % (s.d.)4.6 (21.8)5.4 (21.3)-1.4 (11.3)0.6 (11.4)Year 3, N123110749756Change from baseline in eGFR, mean (s.d.)1.5 (11.6)-0.9 (11.3)0.1-3.3 (10.9)-1.1 (10.7)0.0001Percent change from baseline in eGFR, mean % (s.d.)3.3 (24.2)-1.8 (22.3)-3.8 (13.6)-1.1 (13.5)Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ERN, extended-release niacin. Open table in a new tab Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ERN, extended-release niacin. Within the CKD group, there was a significantly higher rate of discontinuation of ERN compared with placebo (32.7 vs. 22.7%, P=0.01). In the ERN arm, higher rates of flushing, increased glucose, and gastrointestinal symptoms were observed compared with the placebo arm. Specifically for symptomatic flushing/itching, these symptoms accounted for nearly 30% of the primary reason for drug discontinuation in the ERN arm compared with 14% in the placebo arm in the CKD group (Table 6).Table 6Reasons for drug discontinuation by treatment assignmentCKDNo CKDPlaceboNiacinP-valuePlaceboNiacinP-valueN25125414441464Discontinued study drug N (%)57 (22.7%)83 (32.7%)0.012284 (19.7%)353 (24.2%)0.004Primary reason for drug discontinuation Flushing, itching8 (14.0%)25 (30.1%)35 (12.3%)79 (22.4%) Liver function test abnormality0 (0.0%)1 (1.2%)5 (1.8%)4 (1.1%) Patient request22 (36.8%)24 (28.9%)115 (40.5%)102 (29.0%) Nonstudy physician request8 (14.0%)9 (10.8%)27 (9.5%)40 (11.3%) Other clinical reason to discontinue16 (28.1%)13 (15.7%)79 (27.8%)83 (23.5%) Increased glucose2 (3.5%)5 (6.0%)12 (4.2%)24 (6.8%) Gastrointestinal symptoms1 (1.8%)5 (6.0%)11 (3.9%)21 (5.9%)Abbreviation: CKD, chronic kidney disease. Open table in a new tab Abbreviation: CKD, chronic kidney disease. In this secondary analysis from AIM-HIGH, there was no incremental benefit of adding ERN to simvastatin versus placebo in the important, high-risk subset of CKD patients with respect to secondary prevention of cardiovascular events. As expected, the CKD patients had a much higher primary end point than the non-CKD group, indicating a very high residual CVD risk in this subgroup. It is also important to note that most of the noncardiovascular deaths were because of cancer, but no association between niacin treatment and cancer was observed. It is not clear why AIM-HIGH results do not demonstrate the cardiovascular benefit of improvement in HDL-C and TG levels in CKD patients. There are several possibilities: (1) There is no different impact of ERN on cardiovascular outcomes in different levels of renal function in secondary prevention. (2) The impact of the low HDL-C and elevated TG levels is reduced in the context of aggressively treated LDL-C in this subset of patients. (3) Perhaps HDL-C is not the best marker to study clinical outcomes during ERN therapy. In addition, there is still some degree of uncertainty on whether HDL-C is a modifiable cardiac risk factor. (4) It is conceivable that other factors related to decreased kidney function such as elevated fibroblast growth factor-23 levels or other unidentified uremic factors have a more important role on cardiovascular outcomes.8Isakova T. Xie H. Schwartz S. et al.Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.JAMA. 2011; 23: 2432-2439Crossref Scopus (810) Google Scholar From the early stages of CKD, abnormal apolipoprotein metabolism can be demonstrated.9Vaziri N.D. Dicus M. Ho N.D. et al.Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency.Am J Kidney Dis. 2011; 5: 357-372Google Scholar Oxidative stress is part of the complex interplay between CKD and heart disease,10Himmelfarb J. Hakim R. Oxidative stress in uremia.Curr Opin Nephrol Hypertens. 2003; 12: 593-598Crossref PubMed Scopus (154) Google Scholar and is linked to endothelial dysfunction,11Heitzer T. Schlinzig T. Krohn K. et al.Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease.Circulation. 2001; 104: 2673-2678Crossref PubMed Scopus (1656) Google Scholar which is highly prevalent in patients with moderate to severe CKD.12Yilmaz M.I. Saglam M. Caglar K. et al.The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine.Am J Kidney Dis. 2006; 47: 42-50Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 13Kalil R. Flanigan M. Stanford W. et al.Dissociation between progression of coronary artery calcification and endothelial function in hemodialysis patients: A prospective pilot study.Clin Nephrol. 2011; 78: 1-9Crossref Scopus (23) Google Scholar Patients with CKD are at a high risk for CV events.1Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9021) Google Scholar It is conceivable that drugs such as niacin could have a cardioprotective effect in CKD considering their antioxidant properties and effects on endothelial function.9Vaziri N.D. Dicus M. Ho N.D. et al.Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency.Am J Kidney Dis. 2011; 5: 357-372Google Scholar, 14Warnholtz A. Wild P. Ostad M.A. et al.Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: Results of the randomized, double-blind, placebo-controlled INEF study.Atherosclerosis. 2009; 209: 216-221Abstract Full Text Full Text PDF Scopus (69) Google Scholar Recent studies targeting LDL-C for primary prevention in CKD patients who are not on renal replacement therapy such as the Study of Heart and Renal Protection trial demonstrated that LDL-C reduction is cardioprotective.3Biagent C. Landray M.J. Reith C. et al.The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial.Lancet. 2011; 377: 2181-2192Abstract Full Text Full Text PDF PubMed Scopus (1892) Google Scholar A substudy of the Treating to New Targets trial demonstrated a survival benefit with lowering of LDL cholesterol with atorvastatin in CKD.15Shepherd J. Lastelein J.J. Bittner V. et al.Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease; The TNT study.J Am Coll Cardiol. 2008; 51: 1448-1451Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar TGs-lowering agents such as gemfibrozil and fenofibrate have been shown to be cardioprotective in nondialytic CKD patients.16Ting R. Keech A. Drury P. et al.Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment.Diabetes Care. 2012; 35: 218-225Crossref PubMed Scopus (95) Google Scholar, 17Tonelli M. Collins D. Robins S. et al.Veterans Affairs High-Densisty Lipoprotein Intervention Trial (VA-HIT) Investigators.Kidney Int. 2004; 66: 1123-1130Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar These results suggest that LDL has a more important role than HDL-C in CVD in CKD, and that there may be a role for TG, although we could not demonstrate it in our study. Studies testing the inhibition of cholesteryl ester transfer protein such as torcetrapib and dalcetrapib failed to demonstrate improvement in cardiovascular outcomes despite successfully increasing HDL-C levels.18Barter P.J. Caulfield M. Eriksson M. et al.Effects of Torcetrapib in patients at high risk for coronary evens.N J Engl Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2610) Google Scholar, 19Schwartz G.G. Olsson A.G. Abt M. et al.Effects of Dalcetrapib in patients with recent acute coronary syndrome.N Engl J Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1560) Google Scholar The recently completed Second Heart Protection Study Treatment of HDL to Reduce Incidence of Vascular Events study is the largest prospective randomized trial testing niacin in patients at a high risk for CV events to date, and it failed to demonstrate cardioprotective effects.20The HPS2-THRIVE Collaborative GroupEffects of extended-release niacin with laropiprant in high-risk patients.N Engl J Med. 2014; 371: 203-212Crossref PubMed Scopus (1172) Google Scholar Another important end point of this study was to examine the effects of ERN on longitudinal change in kidney function and to assess the tolerability in CKD patients. We observed a slower rate of decline in eGFR in ERN-treated patients when all AIM-HIGH participants were examined together. In non-CKD patients, ERN therapy was also associated with a slower rate of eGFR decline than placebo. These data indicate that ERN slows decline in eGFR in a human trial, extending observations in animals that niacin beneficially affects renal function. However, there was no difference in the rates of eGFR decline in this small subgroup of CKD patients comparing ERN with placebo-treated patients. These results cannot exclude a possible benefit of ERN in kidney function in CKD, because the study was not powered to detect definitive changes in kidney function, and they certainly raise interest for further prospective studies examining ERN as a possible nephroprotective agent, as this is the largest prospective human data published so far demonstrating such an effect. Furthermore, in a recent substudy of the AIM-HIGH trial, Guyton et al.21Guyton J. Slee A. Anderson T. et al.Relationship of lipoprotein to cardiovascular events: the AIM-HIGH trial.J Am Coll Cardiol. 2013; 62: 1580-1584Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar observed a trend toward cardiovascular benefit in the subgroup with the lowest HDL-C and highest TG levels treated with ERN. Whether CKD subjects with these characteristics would receive cardiovascular benefit from ERN is not known. Our findings of high rates of ERN discontinuation in the CKD arm (32%) should be carefully considered in future clinical trials examining the role of ERN in dyslipidemias in patients who are in other stages of CKD. It is possible that worse tolerance of niacin among CKD participants (i.e., niacin-related altered foo