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Abstract: Cardiovascular disease (CVD) is a leading cause of death in Canada, and its risk of development is 3 times greater in those with diabetes mellitus (DM). Fasting low-density lipoprotein cholesterol (LDL-C) is the traditional lipid biomarker used in CVD risk assessment. While lowering LDL-C does reduce CVD risk, substantial residual risk remains and underscores the complex multifactorial nature of the disease. Recent studies in Europe have demonstrated that elevated non-fasting remnant cholesterol (RC) significantly predicts CVD risk, often with greater statistical power than for LDL-C. While Canadian lipid screening guidelines do recommend the measurement of non-fasting lipids, Canadian epidemiological data on non-fasting RC and CVD risk prediction is lacking in individuals with and without DM. The first study in this thesis aimed to determine the relationship between non-fasting RC (compared to LDL-C) and CVD in the Canadian general population, and the second study aimed to determine the relationship between non-fasting RC (compared to other lipids) and CVD in Canadians with and without DM. Alberta’s Tomorrow Project (ATP) is a large prospective Canadian cohort initiated in 2000. Non-fasting lipid data collected from this cohort was linked to Alberta Health administrative databases for individual-level determination of CVD outcomes and covariates such as: statin use, diagnosis of DM, and other comorbidities. The relationship of non-fasting RC (calculated as total cholesterol – LDL-C – high-density lipoprotein cholesterol) and other lipids with a composite of incident CVD was determined by multivariate logistic regression in n=13, 988 eligible participants in the first study, and n=13, 631 eligible participants stratified by DM status in the second study. In the first study, 69.4% of participants were female and had a mean age of 61.8±9.7 years. Mean non-fasting RC was significantly elevated in individuals with CVD (n=1,156; RC 0.87±0.40 mmol/L) compared to individuals without CVD (n=12, 832; RC 0.78±0.38 mmol/L). Conversely, mean LDL-C was moderately decreased in individuals with CVD compared to those without (2.69±0.93 mmol/L and 2.88±0.84 mmol/L, respectively). Accordingly, the odds of incident composite CVD per 1 mmol/L increase of RC were significantly elevated by 48% (adjusted odds ratio (aOR) 1.48; 95% confidence interval (CI) 1.27-1.73), and odds of CVD per 1 mmol/L increase of LDL-C were significantly decreased by 27% (aOR 0.73; 95% CI 0.68-0.79). In the second study, 69.8% of participants were female and had a mean age of 61.6±9.7 years. Individuals with DM (n=881) had significantly higher mean non-fasting RC (0.94±0.41 mmol/L) and proportion of incident CVD diagnoses (12.2%) compared to individuals without DM (n=12, 750, RC 0.77±0.38 mmol/L, CVD 7.4%). In addition, individuals with DM had significantly lower mean LDL-C compared to those without DM (2.22±0.90 mmol/L and 2.92±0.82 mmol/L, respectively). Unit (1 mmol/L) increases of non-fasting RC were significantly associated with increased odds of CVD in individuals without DM (aOR 1.39; 95% CI 1.16-1.65) and tended to be associated with increased odds of CVD in individuals with DM (aOR 1.32; 95% CI 0.79-2.22). Non-fasting RC significantly predicted CVD incidence in the ATP population overall and in those without DM. Similarly, non-fasting RC tended to predict increased CVD risk in participants with DM, although we recognize that the latter observation did not reach statistical significance and had relatively low event rates. Further studies are needed in Canadian populations to determine normal reference ranges for non-fasting RC. However, in light of the rising clinical importance of treating residual CVD risk, non-fasting RC could be considered as a potential screening and treatment target; both in the general population and in those with DM.