Associations between cardiovascular disease, cancer and very low HDL cholesterol in the REasons for Geographical And Racial Differences in Stroke (REGARDS) study. Peter Penson, Leann Long, George Howard, Virginia J. Howard, Steven R. Jones, Seth S. Martin, Dimitri P. Mikhailidis, Paul Muntner, Manfredi Rizzo, Daniel J. Rader, Monika M. Safford, Amirhossein Sahebkar, Peter P. Toth, Maciej Banach

Disclosures I have given talks, attended conferences and participated in studies sponsored by Abbott/Mylan, Actavis, Akcea, Biofarm, Sanofi, MSD, Pfizer, KRKA, Valeant, Abbott Vascular and Amgen. I am a member of International Advisory Board of Amgen, Lilly, Sanofi, Abbott Vascular, Esperion, Akcea, Resverlogix and Daiichi-Sankyo. I have received a research grant from Valeant and Sanofi.

Framingham Heart Study: Low HDL-C Predicts CHD Independent of LDL-C 85 65 45 25 100 160 220 1 2 3 CAD Risk After 4 Years* HDL-C is inversely correlated with CAD risk Correlation is independent of LDL-C HDL-C mg/dL LDL-C, mg/dL This slide, also from Framingham, slightly more recent data, comparing HDL and LDL together and showing that HDL in these observational studies tends to be a stronger risk factor than LDL cholesterol, so surely understanding that a low LDL patient is at high risk even if his or her LDL is completely adequate is an important point. Then the question is whether we should try to intervene and how to intervene, and it remains an open question. Epidemiological studies consistently show low HDL-C to be an independent risk factor for CVD. One example is the Framingham Heart Study, which demonstrated that: HDL-C is an independent predictor of CAD at all levels of LDL-C Levels of HDL-C are inversely related to risk of CAD Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a. *Men aged 50-70 years

Emerging Risk Factor Collaboration meta-analysis Each standard deviation increase in HDL-C (15 mg/dL) was related to a 22% decrease in coronary heart disease (CHD) risk (for patients with HDL-C between 20-80 mg/dl) The Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000.

Association of an HDL-C genetic variant (LIPG Ans396Ser) with MI in 116,320 participants from 20 studies (PROCARDIS Consortium) Procardis Consortium made a Mendellian analysis of 20 studies involving 116,320 participants. The study showed that a genetic variant LIPG Ans396Ser is strongly associated with increased HDL-C levels. However, despite a 5.5 mg/dl HDL-C increase, there was no significant association between the genetic variant and incidence of myocardial infarction with an Odds Ratio of 0.99. The study concludes that genetically raising HDL-C does not correlate with a decrease in the incidence of myocardial infarction. Voight BF et al, Lancet,17 May, 2012

Jafri et al. reported a significant inverse association between baseline HDL-C and the rate of incident cancer (p =0.018). The inverse association persisted after adjusting for baseline lLDL-C, age, BMI, DM, sex, and smoking status. For every 10-mg/dl increment in HDL-C, there was a 36% (95%Cl: 24% to 47%) relatively lower rate of the development of cancer (p <0.001). Tada H, et al. J Clin Lipidol 2016;10(6):1311-1317. Jafri H, et al. J Am Coll Cardiol. 2010;55(25):2846-54.

Purpose We analyzed data from the REasons for Geographical And Racial Differences in Stroke (REGARDS) study to investigate the relationships between low (30 to 39.9 mg/dL) and very low (<30 mg/dl) concentrations of HDL-C and incident all-cause-mortality, death from malignant disease, and with fatal or non-fatal incident coronary heart disease (CHD).

Eligibility criteria included: black or white race, aged 45 and older, absence of conditions associated with a life expectancy of less than 5 years. Potential participants with diagnosed malignancy at baseline were excluded, those with medical conditions that would preclude long-term participation, and being cognitive impairment. The participation rate was estimated as 33%, similar to other studies. Participants were selected from commercially available lists and recruited through a combination of mail and telephone contact. Because of a focus on geographic and racial disparities in stroke mortality, Blacks were oversampled (44%), as were residents of the southeastern U.S. Stroke Belt states (56%). Howard VJ, et al. Neuroepidemiology. 2005;25(3):135-43. Morton LM, et al. Am J Epidemiol. 2006;163(3):197-203.

Methods: Inclusion criteria In this analysis, we included REGARDS study participants who: fasted overnight prior to their study visit, were not missing any explanatory variables of interest, had valid measurements of total cholesterol, HDL-C and triglycerides. REGARDS participants with a history of CHD at baseline were excluded from the incident CHD analysis. To assess the association between the HDL-C categories and each outcome, a series of incremental Cox proportional hazards models were employed on complete cases. Because the complete case method of analysis has been shown to underestimate risks, especially in black women, we then reanalyzed the data, imputing missing values using multiple imputation with chained equations (MICE).

Methods: Endpoints The three following endpoints were investigated: death from any cause, death from malignant disease (both assessed through semi-annual telephone follow up, death information from participant proxies, linkages with the Social Security Death Index (SSDI) as well as the National Death Index (NDI)), and, incident fatal or non-fatal CHD, each at or before December 31, 2013 (the last date where adjudication of the cause of death was available).

Of the 22,063 participants that met the complete case inclusion criteria 45% of them were male and 39% were black. The mean age was 64.6 (±9.4) years. With respect to HDL-C, 763 (3.5%) participants were in the very low (<30 mg/dL) HDL-C category; 4105 (18.6%) in the low (30 - <40 mg/dL), and 17195 (77.9%) were in the normal (≥40 mg/dl) category. Participants in the low and very low HDL categories were more likely to be male, white, and to have diabetes than participants with normal HDL. HDL category was directly correlated with LDL-C and inversely correlated with triglycerides.

Unadjusted Kaplan-Meier curves showed that, compared with participants in the normal HDL-C category, all-cause mortality was higher, rate of cancer mortality was increased rates of incident CHD were increased (apparent before 2 years and extend through 10 years of follow up for both), in patients with low, or very low HDL-C.

There is no evidence that the association between HDL-C category and all-cause mortality, cancer-specific mortality, and incident CHD varies change over time (p=0.19; p=0.06; p=0.09, respectively).

Conclusions Low HDL-C was associated with increased risk for all-cause mortality, cancer mortality, and incident CHD in a minimally-adjusted model, however the effect was attenuated in fully-adjusted model. When complete case analysis was used, for all three outcomes considered, the sex-HDL-C interaction was significant with poorer outcomes associated with low HDL-C in women than men. Further, the relationship with cancer mortality appears to be specific to women. Using both complete case analysis and MICE, we observed the existence of an ‘HDL paradox’, whereby low HDL-C associated with lower risk of incident CHD was observed in black participants of the REGARDS study.