Abstract
Background
Non-high-density lipoprotein cholesterol (HDL-C) is increasingly incorporated into guidelines along with low-density lipoprotein cholesterol (LDL-C) to guide lipid-lowering therapy decisions.
Objectives
The purpose of this study was to examine patterns of LDL-C and non-HDL-C levels after statin initiation for primary prevention and their association with incident cardiovascular events.
Methods
This was a population-based cohort study in Ontario, Canada, among persons aged ≥66 years starting a statin for primary prevention between January 1, 2012, and December 31, 2019. We identified those with a lipid panel in the 1-year after starting a statin and categorized individuals based on LDL-C and non-HDL-C thresholds for intensification in the 2021 Canadian Cardiovascular Society dyslipidemia guidelines. We stratified by diabetes/chronic kidney disease (CKD) status. The primary outcome was the composite of all-cause mortality or cardiovascular events, with follow-up to December 31, 2020. We used a Cox proportional hazards model for analysis.
Results
Our cohort comprised 125,013 people. The median follow-up was 2.5 years. Compared with those meeting both LDL-C and non-HDL-C thresholds, being above both thresholds was associated with an increased rate of the primary outcome for people without diabetes/CKD (HR: 1.10; 95% CI: 1.05-1.15) and for those with diabetes/CKD (HR: 1.16; 95% CI: 1.09-1.23). Being below the LDL-C threshold but above non-HDL-C threshold was associated with an increased rate of the primary outcome for people with diabetes/CKD (HR: 1.16; 95% CI: 1.03-1.30).
Conclusions
These findings support the residual risk associated with incompletely controlled LDL-C or non-HDL-C levels after statin initiation for primary prevention.
Key words: clinical practice guideline, lipids, primary prevention, statins
Central Illustration
Low-density lipoprotein cholesterol (LDL-C) has been the traditional focus in predicting cardiovascular (CV) risk, but assessing LDL-C alone may not capture the atherogenic potential of other lipoproteins. Nonhigh-density lipoprotein cholesterol (HDL-C) is a measure of the cholesterol content in atherogenic lipoproteins, which include very low-density lipoproteins, intermediate density lipoproteins, lipoprotein(a), and LDL.1 Non-HDL-C has been associated with the risk of atherosclerotic cardiovascular disease (ASCVD)1,2 and the strength of association between non-HDL-C and major cardiovascular events has been suggested to be greater than the association with LDL-C.2 Non-HDL-C could also theoretically be preferred to LDL-C in guiding lipid-lowering therapy decisions given the limitations and variability of calculated LDL-C.3,4
American dyslipidemia guidelines discuss the atherogenic potential of non-HDL-C but do not incorporate non-HDL-C treatment thresholds for primary prevention, instead focusing on percent LDL-C lowering5 (though the 2022 ACC expert consensus decision pathway for nonstatin therapies includes non-HDL-C thresholds).6 Although primary prevention risk calculators (eg, 2013 American College of Cardiology/ American Heart Association Pooled Risk, 2024 Predicting Risk of Cardiovascular Disease Events [PREVENT])7,8 incorporate non-HDL-C levels indirectly by including total cholesterol and HDL-C, none require explicit knowledge or reflection on inputting a non-HDL result into the calculator to estimate risk. As a result, to most clinicians in routine practice, the importance of non-HDL levels in risk estimates may remain unclear. European and Canadian clinical practice guidelines incorporate non-HDL-C thresholds for intensification into their treatment algorithms, along with LDL-C thresholds.9 The Canadian Cardiovascular Society’s (CCS) 2021 dyslipidemia guideline suggests that in primary prevention, a person with intermediate CV risk should be offered a statin when LDL-C is ≥135 mg/dL (3.5 mmol/L) or non-HDL-C ≥162 mg/dL (4.2 mmol/L). If a statin is initiated and LDL-C remains ≥77 mg/dL (2.0 mmol/L) or non-HDL-C >100 mg/dL (2.6 mmol/L), dose adjustment or add-on therapy could then be considered.9 In the European Society of Cardiology guidelines, non-HDL-C is a secondary lipid target particularly in persons with diabetes or chronic kidney disease (CKD).10 Examining the association between non-HDL-C and LDL-C levels following statin initiation and CV risk can help elucidate the real-world implications of guideline recommendations that include non-HDL-C. We hypothesize that there is residual risk associated with achieved LDL-C below guideline-directed thresholds for intensification in the setting of non-HDL-C above recommended thresholds. Therefore, we sought to examine patterns of LDL-C and non-HDL-C lipid levels after statin initiation for primary prevention and their association with CV outcomes.
Methods
We conducted a population-based cohort study in Ontario, Canada, using linked health care administrative data among persons ≥66 years of age.
Data sources
We used health care administrative data sets at ICES (formerly the Institute for Clinical Evaluative Sciences), an independent, nonprofit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement. Information on diabetes status was obtained from the Ontario Diabetes Database.11 Sociodemographic data were obtained from the Ontario Registered Persons Database. Information on diagnoses was obtained from the Canadian Institute for Health Information Discharge Abstract Database, the Canadian Institute for Health Information National Ambulatory Care Reporting System, and the Ontario Health Insurance Plan Physician Claims database. Laboratory data were obtained from the Ontario Laboratories Information System. Frailty status was calculated using the Hospital Frailty Risk Score.12 Prescription drug use data were ascertained from the Ontario Drug Benefit Database, which provides dispensed prescription medication data for medications on the provincial formulary in Ontario for those ≥65 years of age. Outcome data were obtained from Discharge Abstract Database and Registered Persons Database. A detailed description of data sets used, and definitions, is in Supplemental Table 1. Data sets were linked using unique encoded identifiers and analyzed at ICES.
Population
We identified all Ontarians aged ≥66 years with no history of CVD (Supplemental Table 1) and who initiated a statin between January 1, 2012, and December 31, 2019. Statin initiation was defined as not having filled a statin prescription in the previous year. We included people who survived event-free ≥1 year after the statin was started and who had a lipid panel performed in the 1-year period after the statin was started. We excluded individuals who were on chronic dialysis (in the 5 years before index [1 year following statin initiation]) or resided in long-term care. We conducted separate analyses for people with a history of diabetes or CKD (Supplemental Table 1; these groups are considered to have the same lipid goals in the CCS guidelines) and those without.
Exposures
The index date was 1 year following statin initiation. We identified the most recent lipid panel in the year prior to the index date (ie, the year after starting statins). From these lipid panels, we categorized individuals based on LDL-C and non-HDL-C targets in the 2021 CCS dyslipidemia guidelines (Table 1).9
Table 1.
Lipid Categories Based on Thresholds for Intensification in 2021 CCS Dyslipidemia Guidelines
| Without Diabetes or CKD | With Diabetes or CKDa |
|---|---|
| LDL-C <97 mg/dL (2.5 mmol/L) and non-HDL-C <124 mg/dL (3.2 mmol/L) (ref) | LDL-C <77 mg/dL (2 mmol/L) and non-HDL-C <100 mg/dL (2.6 mmol/L) (ref) |
| LDL-C ≥97 mg/dL (2.5 mmol/L) and non-HDL <124 mg/dL (3.2 mmol/L) | LDL-C ≥77 mg/dL (2 mmol/L) and non-HDL-C <100 mg/dL (2.6 mmol/L) |
| LDL-C <97 mg/dL (2.5 mmol/L) and non-HDL ≥124 mg/dL (3.2 mmol/L) | LDL-C <77 mg/dL (2 mmol/L) and non-HDL-C ≥100 mg/dL (2.6 mmol/L) |
| LDL-C ≥97 mg/dL (2.5 mmol/L) and non-HDL ≥124 mg/dL (3.2 mmol/L) | LDL-C ≥77 mg/dL (2 mmol/L) and non-HDL-C ≥100 mg/dL (2.6 mmol/L) |
CCS = Canadian Cardiovascular Society; CKD = chronic kidney disease; non-HDL-C = nonhigh-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; ref = reference category.
These categories were also applied to those without diabetes or CKD in the post hoc analysis.
Outcomes
The primary outcome was the composite of all-cause mortality, hospitalization for myocardial infarction (MI) or stroke, and coronary revascularization (Supplemental Table 1). Secondary outcomes were individual components of the primary outcome. Individuals were followed until December 31, 2020, or an outcome of interest.
Analysis
We stratified our analyses based on the presence or absence of diabetes or CKD. We described baseline characteristics using descriptive statistics. We reported the proportion of statin use at index (defined as filling a statin prescription in the 180 days before index). To examine the association between each LDL-C/non-HDL-C category and outcomes of interest, we used a Cox proportional hazards model adjusted for covariates. For those without diabetes or CKD, the reference category was LDL-C <97 mg/dL (2.5 mmol/L) and non-HDL-C <124 mg/dL (3.2 mmol/L). We chose this threshold to allow for more lenient goals in people who may be at lower CV risk but were started on statin therapy due to LDL-C ≥135 mg/dL (3.5 mmol/L) or non-HDL-C ≥162 mg/dL (4.2 mmol/L). For those with diabetes or CKD, the reference was LDL-C <77 mg/dL (2 mmol/L) and non-HDL-C <100 mg/dL (2.6 mmol/L), as per the 2021 CCS guidelines. We adjusted for age, sex, rural residence, neighborhood marginalization index quintile, hypertension, liver disease, cancer, HIV, lung disease, autoimmune disease, transplant history, mental health disorder, thyroid disorder, frailty status, statin intensity (high vs low/moderate based on initial dose), most recent LDL-C before statin initiation, most recent non-HDL-C before statin initiation, and concomitant medication use (antihypertensives, diabetes medications [for those with diabetes/CKD], ezetimibe); see Supplemental Table 1 for definitions. We reported crude and adjusted effects with corresponding 95% CIs. Relative effects were reported as HRs. The adjusted rate differences (RDs) were calculated using a log-linked Poisson model adjusted for potential confounders. We calculated the difference in adjusted rates by estimating a nonlinear function of the model parameters. We checked for overdispersion, and if overdispersion was observed we reran models using scale = deviance.
We also performed a prespecified analysis where we examined the association between non-HDL-C as a continuous variable and the outcomes of interest using a Cox regression model (adjusting for factors specified above and LDL-C as a continuous variable). For the secondary outcomes (apart from all-cause mortality), we used cause-specific hazards models to account for the competing risk of death. We performed a post hoc analysis among persons without diabetes/CKD, where we applied thresholds based on LDL-C <77 mg/dL (2 mmol/L) and non-HDL-C 100 mg/dL (2.6 mmol/L) (Table 1). We also performed a post hoc analysis where we tested for the interaction between lipid category and presence of diabetes/CKD vs no diabetes/CKD (using a threshold of P < 0.05 for significance).
Permissions
This data set was created at ICES under section 45 of Ontario’s Personal Health Information Protection Act, which did not require Research Ethics Board review. Patients or public were not involved in the design, conduct, reporting, or dissemination of our research.
Results
We identified 253,478 people ≥66 years of age initiated on statins in the study period. A total of 11,137 died in the 1-year period after a statin was started. After excluding applying exclusions, there were 173,127 people. In the 1-year period after statin initiation, 72% (n = 125,013) of people had a lipid panel performed. The median number of days from statin initiation to the first lipid panel was 211 (Q1-Q3: 98-303) days. Among those without diabetes or CKD, the proportion of people with a lipid panel in the 1-year period after statin initiation was 70% compared to 81% among those with diabetes or CKD.
Baseline characteristics
Baseline characteristics are in Table 2, Table 3, including the proportion of statin use at index. Among those without diabetes or CKD, the median age was 75 (Q1-Q3: 72-79) years, and 56% were female. Of the 94,905 people with a lipid panel, 66,099 (70%) had both an LDL-C and non-HDL-C below the thresholds for intensification, while 22,043 (23%) were above both thresholds, and 2,413 (3%) had a non-HDL-C above threshold with an LDL-C below threshold. In those with diabetes or CKD, the median age was 77 (Q1-Q3: 73-81) years, and 56% were female. Of the 30,108 with a lipid panel, 17,103 (57%) had both an LDL-C and non-HDL-C below threshold, while 9,809 (33%) were above both thresholds, and 1,911 (6%) were above the non-HDL-C threshold but below the LDL-C threshold.
Table 2.
Characteristics of Persons Without Diabetes or Chronic Kidney Disease
| Overall (N = 135,829) | LDL-C <97 mg/dL Non-HDL-C <124 mg/dL (n = 66,099) |
LDL-C ≥97 mg/dL Non-HDL-C <124 mg/dL (n = 3,624) | LDL-C <97 mg/dL Non-HDL-C ≥124 mg/dL (n = 2,413) | LDL-C ≥97 mg/dL Non-HDL-C ≥124 mg/dL (n = 22,043) | No Lipid Panel (n = 41,650) | |
|---|---|---|---|---|---|---|
| Age, y | 75 (72-79) | 75 (72-79) | 75 (71-79) | 74 (71-77) | 75 (72-78) | 76 (72-80) |
| Female | 76,167 (56.1%) | 35,335 (53.5%) | 2,131 (58.8%) | 1,383 (57.3%) | 14,029 (63.6%) | 23,289 (55.9%) |
| Ruralitya | ||||||
| Missing | 4,375 (3.2%) | 2,084 (3.2%) | 128 (3.5%) | 67 (2.8%) | 675 (3.1%) | 1,421 (3.4%) |
| Large urban | 107,485 (79.1%) | 52,609 (79.6%) | 2,952 (81.5%) | 1,838 (76.2%) | 17,803 (80.8%) | 32,283 (77.5%) |
| Medium urban | 10,795 (7.9%) | 5,171 (7.8%) | 227 (6.3%) | 238 (9.9%) | 1,619 (7.3%) | 3,540 (8.5%) |
| Small town | 13,174 (9.7%) | 6,235 (9.4%) | 317 (8.7%) | 270 (11.2%) | 1,946 (8.8%) | 4,406 (10.6%) |
| Marginalization indexb | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) |
| Medical conditions | ||||||
| Hypertension | 95,079 (70.0%) | 47,779 (72.3%) | 2,408 (66.4%) | 1,741 (72.2%) | 14,792 (67.1%) | 28,359 (68.1%) |
| Autoimmune disease | 6,960 (5.1%) | 3,537 (5.4%) | 210 (5.8%) | 112 (4.6%) | 1,124 (5.1%) | 1,977 (4.7%) |
| Lung disease | 17,588 (12.9%) | 8,399 (12.7%) | 440 (12.1%) | 301 (12.5%) | 2,765 (12.5%) | 5,683 (13.6%) |
| Thyroid disorder | 119,628 (88.1%) | 57,924 (87.6%) | 3,148 (86.9%) | 2,130 (88.3%) | 18,937 (85.9%) | 37,489 (90.0%) |
| Mental health disorder | 54,826 (40.4%) | 26,596 (40.2%) | 1,381 (38.1%) | 965 (40.0%) | 8,116 (36.8%) | 17,768 (42.7%) |
| Dementia | 7,277 (5.4%) | 3,314 (5.0%) | 205 (5.7%) | 79 (3.3%) | 887 (4.0%) | 2,792 (6.7%) |
| LDL-C before index date, mmol/L | 1.95 (1.53-2.58) | 1.70 (1.38-2.01) | 2.61 (2.55-2.69) | 2.30 (2.10-2.42) | 3.26 (2.91-3.76) | 1.72 (1.29-2.18) |
| Non-HDL-C before index, mmol/L | 2.54 (2.06-3.25) | 2.25 (1.91-2.59) | 3.06 (2.97-3.13) | 3.37 (3.27-3.55) | 3.97 (3.56-4.52) | 4.00 (2.89-4.92) |
| LDL-C before statin initiation, mmol/L | 3.37 (2.80-3.98) | 3.25 (2.69-3.81) | 3.65 (2.97-4.28) | 3.48 (2.80-4.19) | 3.80 (3.26-4.37) | 3.32 (2.70-3.95) |
| Non-HDL-C before statin initiation, mmol/L | 4.08 (3.43-4.74) | 3.92 (3.31-4.55) | 4.17 (3.45-4.86) | 4.62 (3.84-5.35) | 4.53 (3.95-5.17) | 4.04 (3.34-4.73) |
| High-dose statin | 17,491 (12.9%) | 9,116 (13.8%) | 301 (8.3%) | 208 (8.6%) | 2,022 (9.2%) | 5,844 (14.0%) |
| On statin at index (%) | 80,978 (59.6%) | 49,252 (74.5%) | 1,908 (52.6%) | 1,425 (59.1%) | 7,750 (35.2%) | 20,643 (49.6%) |
Abbreviations as in Table 1.
Values are median (Q1-Q3) or n (%). 97 mg/dL LDL-C = 2.5 mmol/L and 124 mg/dL non-HDL-C = 3.2 mmol/L.
Large urban >100,000 persons, medium urban 10,000 to 100,000 persons, small town <10,000 persons.
Score from 1 (least marginalized) to 5 (most marginalized).
Table 3.
Characteristics of Persons With Diabetes or Chronic Kidney Disease
| Overall (N = 37,298) | LDL-C <77 mg/dL Non-HDL-C <100 mg/dL (n = 17,103) | LDL-C ≥77 mg/d Non-HDL-C <100 mg/dL (n = 936) | LDL-C <77 mg/dL Non-HDL-C ≥100 mg/dL (n = 1,911) | LDL-C ≥77 mg/dL Non-HDL-C ≥100 mg/dL (n = 9,809) | No Lipid Panel (n = 7,539) | |
|---|---|---|---|---|---|---|
| Age, y | 77 (73-81) | 77 (73-81) | 76 (73-81) | 76 (73-80) | 76 (73-81) | 78 (74-83) |
| Female | 20,821 (55.8%) | 8,882 (51.9%) | 523 (55.9%) | 1,085 (56.8%) | 6,071 (61.9%) | 4,260 (56.5%) |
| Ruralitya | ||||||
| Missing | 981 (2.6%) | 423 (2.5%) | 17 (1.8%) | 59 (3.1%) | 259 (2.6%) | 223 (3.0%) |
| Large urban | 30,669 (82.2%) | 14,211 (83.1%) | 773 (82.6%) | 1,536 (80.4%) | 8,186 (83.5%) | 5,963 (79.1%) |
| Medium urban | 2,716 (7.3%) | 1,199 (7.0%) | 71 (7.6%) | 156 (8.2%) | 649 (6.6%) | 641 (8.5%) |
| Small town | 2,932 (7.9%) | 1,270 (7.4%) | 75 (8.0%) | 160 (8.4%) | 715 (7.3%) | 712 (9.4%) |
| Marginalization indexb | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) | 3.25 (2.50-3.75) | 3.00 (2.50-3.75) | 3.00 (2.50-3.75) |
| Medical conditions | ||||||
| Hypertension | 28,470 (76.3%) | 13,182 (77.1%) | 709 (75.7%) | 1,464 (76.6%) | 7,424 (75.7%) | 5,691 (75.5%) |
| Diabetes | 19,729 (52.9%) | 9,632 (56.3%) | 480 (51.3%) | 1,074 (56.2%) | 4,886 (49.8%) | 3,657 (48.5%) |
| Autoimmune disease | 2,081 (5.6%) | 923 (5.4%) | 64 (6.8%) | 88 (4.6%) | 553 (5.6%) | 453 (6.0%) |
| Cancer | 6,326 (17.0%) | 2,886 (16.9%) | 156 (16.7%) | 319 (16.7%) | 1,600 (16.3%) | 1,365 (18.1%) |
| CKD | 20,119 (53.9%) | 8,869 (51.9%) | 502 (53.6%) | 1,034 (54.1%) | 5,516 (56.2%) | 4,198 (55.7%) |
| Lung disease | 5,379 (14.4%) | 2,376 (13.9%) | 129 (13.8%) | 267 (14.0%) | 1,351 (13.8%) | 1,256 (16.7%) |
| Thyroid disorder | 4,398 (11.8%) | 1,919 (11.2%) | 131 (14.0%) | 210 (11.0%) | 1,312 (13.4%) | 826 (11.0%) |
| Mental health disorder | 20,205 (54.2%) | 8,999 (52.6%) | 537 (57.4%) | 1,049 (54.9%) | 5,604 (57.1%) | 4,016 (53.3%) |
| Dementia | 2,261 (6.1%) | 997 (5.8%) | 56 (6.0%) | 81 (4.2%) | 488 (5.0%) | 639 (8.5%) |
| LDL-C before index date, mmol/L | 1.73 (1.33-2.31) | 1.41 (1.14-1.65) | 2.08 (2.03-2.14) | 1.78 (1.60-1.90) | 2.67 (2.32-3.24) | 1.85 (1.24-2.90) |
| Non-HDL-C before index, mmol/L | 2.38 (1.93-3.04) | 1.99 (1.71-2.24) | 2.50 (2.42-2.55) | 2.79 (2.68-2.97) | 3.41 (2.98-4.04) | 3.80 (2.92-4.61) |
| LDL-C before statin initiation, mmol/L | 3.10 (2.54-3.68) | 2.90 (2.41-3.40) | 3.29 (2.73-3.89) | 3.18 (2.58-3.72) | 3.50 (2.94-4.11) | 3.01 (2.42-3.61) |
| Non-HDL-C before statin initiation, mmol/L | 3.88 (3.25-4.55) | 3.64 (3.08-4.22) | 3.84 (3.19-4.47) | 4.31 (3.68-4.98) | 4.30 (3.68-4.97) | 3.82 (3.14-4.53) |
| High-dose statin | 4,621 (12.4%) | 2,399 (14.0%) | 75 (8.0%) | 201 (10.5%) | 844 (8.6%) | 1,102 (14.6%) |
| On statin at index | 25,105 (67.3%) | 13,746 (80.4%) | 647 (69.1%) | 1,444 (75.6%) | 4,839 (49.3%) | 4,429 (58.7%) |
Abbreviations as in Table 1.
Values are median (Q1-Q3) or n (%). 77 mg/dL LDL-C = 2 mmol/L and 100 mg/dL non-HDL-C = 2.6 mmol/L.
Large urban >100,000 persons, medium urban 10,000 to 100,000 persons, small town <10,000 persons.
Score from 1 (least marginalized) to 5 (most marginalized).
Persons without diabetes or CKD
The median follow-up time was 2.9 years (IQR: 3.1 years). Outcome data are reported in Table 4 and the Central Illustration. The adjusted rate of the primary outcome was 26 per 1,000 person-years for the reference group (LDL-C <97 mg/dL [2.5 mmol/L] and non-HDL-C <124 mg/dL [3.2 mmol/L]). For those with an LDL-C ≥97 mg/dL and non-HDL-C <124 mg/dL, the RD was 2.6 per 1,000 person-years (95% CI: 0.05-5.2) and the HR was 1.10 (95% CI: 1.00-1.21) compared with the reference group. For those with an LDL-C ≤97 mg/dL and a non-HDL ≥124 mg/dL, the RD was 1.2 per 1,000 person-years (95% CI: −1.9 to 4.4) and the HR was 1.05 (95% CI: 0.93-1.17) compared with the reference group. Finally, among those with LDL-C ≥97 mg/dL and non-HDL-C ≥124 mg/dL, the RD was 2.5 per 1000 person-years (95% CI: 1.3-3.7) and the HR was 1.10 (95% CI: 1.05-1.15) compared with the reference group. Data for secondary outcomes are in Figure 1 and Supplemental Tables 2 to 5.
Table 4.
The Association Between Lipid Category and the Composite of All-Cause Mortality or Hospitalization for Myocardial Infarction, Stroke, or Revascularization
| Target (mmol/L) | n | Crude Rate per 1,000 Person-Years | Adjusted Rate per 1,000 Person-Years | Adjusted Rate Difference per 1,000 Person-Years (95% CI) | Adjusted HR (95% CI) |
|---|---|---|---|---|---|
| Without Diabetes or CKD | |||||
| LDL-C <97 mg/dL non-HDL-C <124 mg/dL | 66,099 | 33 | 26 | Ref | Ref |
| LDL-C ≥97 mg/dL non-HDL-C <124 mg/dL | 3,624 | 32 | 29 | 2.6 (0.05-4.7) | 1.10 (1.00-1.21) |
| LDL-C <97 mg/dL non-HDL-C ≥124 mg/dL | 2,413 | 30 | 27 | 1.2 (−1.4 to 3.8) | 1.05 (0.93-1.17) |
| LDL-C ≥97 mg/dL non-HDL-C ≥124 mg/dL | 22,043 | 30 | 29 | 2.5 (1.5-3.5) | 1.10 (1.05-1.15) |
| With diabetes or CKD | |||||
| LDL-C <77 mg/dL non-HDL-C <100 mg/dL | 17,103 | 45 | 37 | Ref | Ref |
| LDL-C ≥77 mg/dL non-HDL-C <100 mg/dL | 936 | 46 | 39 | 2.5 (−2.7 to 7.7) | 1.07 (0.92-1.24) |
| LDL-C <77 mg/dL non-HDL-C ≥100 mg/dL | 1,911 | 46 | 42 | 5.7 (1.4-10) | 1.16 (1.03-1.30) |
| LDL-C ≥77 mg/dL non-HDL-C ≥100 mg/dL | 9,809 | 45 | 42 | 5.7 (3.4-8.0) | 1.16 (1.09-1.23) |
RD = rate difference; other abbreviations as in Table 1.
97 mg/dL LDL-C = 2.5 mmol/L and 124 mg/dL non-HDL-C = 3.2 mmol/L.
77 mg/dL LDL-C = 2 mmol/L and 100 mg/dL non-HDL-C = 2.6 mmol/L.
Central Illustration.
Among Persons ≥66 Years of Age Starting Statins for Primary Prevention, We Examined Lipids in the 1-Year Period After Starting Statins and Evaluated the Residual Risk Associated with Being Above Guideline-Directed Thresholds for LDL-C and Non-HDL-C
Being above both thresholds was associated with higher risk of adverse outcomes compared with being below both thresholds among individuals with or without diabetes/CKD. Among those with diabetes/CKD, being below LDL-C but above the non-HDL-C threshold was also associated with residual risk, highlighting the importance of non-HDL-C in this population. CCS = Canadian Cardiovascular Society; other abbreviations as in Figure 1.
Figure 1.
Association Between Being Above Intensification Thresholds and Outcomes
The adjusted HRs and 95% CIs for the composite outcome and each component of the composite outcome among people (A) above both LDL-C and non-HDL-C thresholds for intensification compared to having both measures below guideline-recommended thresholds and (B) below LDL-C threshold but above non-HDL-C threshold. CKD = chronic kidney disease; HDL-C = high-density lipoprotein cholesterol; MI = myocardial infarction; LDL-C = low-density lipoprotein cholesterol.
Persons with diabetes or CKD
The median follow-up time was 2.5 years (IQR: 3.1 years). Outcome data are reported in Table 4. The adjusted rate of the primary outcome was 37 per 1,000 person-years for the reference group (LDL-C <77 mg/dL [2 mmol/L] and non-HDL-C <100 mg/dL [2.6 mmol/L]). For those with an LDL-C ≥77 mg/dL and a non-HDL-C <100 mg/dL, the RD was 2.5 per 1,000 person-years (95% CI: -3.3-8.4) and the HR was 1.07 (95% CI: 0.92-1.24) compared with the reference group. Among those with LDL-C <77 mg/dL but non-HDL ≥100 mg/dL, the RD was 5.7 per 1,000 person-years (95% CI: 0.87-11) and the HR was 1.16 (95% CI: 1.03-1.30) compared with the reference group. Finally, for those with LDL-C ≥77 mg/dL and non-HDL-C ≥100 mg/dL, the RD was 5.7 per 1,000 person-years (95% CI: 3.2-8.3) and the HR was 1.16 (95% CI: 1.09-1.23) compared with the reference group. Data for secondary outcomes are in Figure 1 and Supplemental Tables 2 to 5.
Additional analyses
We also examined the association between non-HDL-C as a continuous variable and the outcomes of interest. In those without diabetes or CKD, increasing non-HDL-C was not associated with the primary outcome (HR: 1.05; 95% CI: 0.97-1.15). In those with diabetes or CKD, increasing non-HDL-C was associated with the primary outcome (HR: 1.17; 95% CI: 1.04-1.32). In a post hoc analysis among persons without diabetes or CKD, applying thresholds based on LDL-C <77 mg/dL (2 mmol/L) and non-HDL-C <100 mg/dL (2.6 mmol/L) did not change findings (Supplemental Table 6). A post hoc test for the interaction between lipid category and diabetes/CKD was not statistically significant (P = 0.092).
Discussion
Summary of findings
The majority of statin initiators in our study met guideline-directed lipid goals, though a portion remained above both the LDL-C and non-HDL-C thresholds for intensification, and a smaller portion had a non-HDL-C above threshold but an LDL-C below threshold. The proportion of people with lipids above threshold was higher among those with diabetes or CKD. We found that having both an LDL-C and a non-HDL-C above guideline-directed thresholds for intensification was associated with an increased rate of adverse CV outcomes. For people with diabetes or CKD, having an LDL-C below threshold but a non-HDL-C above threshold was associated with higher rates of adverse CV outcomes. This observation was not seen among patients without diabetes or CKD, though an interaction test by diabetes or CKD status was not significant. These findings support the residual risk associated with incompletely controlled LDL-C or non-HDL-C levels after initiating statins for primary prevention.
Comparison with existing literature
Non-HDL-C has been associated with risk of ASCVD previously. A 2019 multinational cohort study demonstrated that increasing non-HDL-C concentrations were associated with higher rates of 30-year CVD.1 The authors found that risk was higher among people with diabetes. However, there were relatively few statin users in this cohort. A 2012 meta-analysis2 did examine lipid patterns in people treated with statins and found that on-treatment non-HDL-C and LDL-C were both associated with risk of CV events. The authors concluded that non-HDL-C had a stronger association with future CV events compared to LDL-C. These studies support the association between non-HDL-C and LDL-C levels and CV risk, but do not specifically explore association with specific non-HDL-C or LDL-C levels (as advised in guidelines).
The residual risk of incomplete control of non-HDL-C in the context of controlled LDL-C has been explored by 2 recent studies in Denmark. One study of 13,015 statin-treated patients from the general population found that a non-HDL-C above the sample median was associated with residual risk of mortality and MI even with LDL-C below median.13 In secondary prevention, a cohort study conducted in Denmark found that among persons with LDL-C at target (≤70 mg/dL [1.8 mmol/L]), a non-HDL-C ≥97 mg/dL (2.5 mmol/L) was associated with increased risk of MI, ASCVD, and death.14 To our knowledge, no studies have explored guideline-directed non-HDL-C thresholds after statin initiation and the association with incident CV events in primary prevention. Thus, our findings add to existing literature.
There remains debate around a treat-to-target approach vs simply initiating a moderate or high-intensity statin depending on CV risk. The Canadian Patients Experience Evidence Research (PEER) simplified lipid guideline15 recommends against repeat lipid testing and use of lipid targets/thresholds, and U.S. guidelines moved away from lipid targets in 2013 with more recent guidelines incorporating percent LDL-C lowering.16 In 2023, the U.S. National Lipid Association and American Society for Preventive Cardiology advocated for use of LDL-C targets.17 A treat-to-target approach is centered around analyses that show lower risk of CV events with lower achieved LDL-C levels in statin randomized controlled trials (RCTs).18,19 There is a lack of RCT evidence demonstrating whether targeting specific lipid levels is superior to simply initiating statins in primary prevention. Among patients with coronary artery disease, a 2023 RCT20 found that a treat-to-target approach was noninferior to high-dose statins in reducing risk of adverse CV events. It is argued that a treat-to-target approach may allow for tailored therapy (eg, use of moderate dose statins to achieve lipid targets in patients at >20% 10-year CVD risk). While our study cannot show which approach is best, we found that 20% to 30% of patients remain above guideline-directed thresholds for intensification with initial statin therapy and that there is an associated risk of adverse CV events associated with this. Given a small portion were on high-intensity statins, increasing statin doses could be considered without the need for a second agent.
Absolute risk associated with being above threshold was greater for people at higher baseline risk (people with diabetes or CKD), which is consistent with existing data on benefit of statins.21 One reason non-HDL-C may be preferred in patients with diabetes or CKD is because LDL-C only takes into account cholesterol concentration and not number of particles.22,23 Furthermore, diabetes may also lead to an increase in triglycerides (TGs) which can make LDL-C estimation inaccurate.24 This is also the case for persons with CKD, who often have high TG levels which may skew calculated LDL-C.25 This underscores that relying on LDL-C levels alone may be insufficient. Both diabetes and CKD have been shown to change lipoprotein composition, shifting lipoproteins to have a more atherogenic profile and potentially enhancing the risk of having elevated non-HDL-C.25,26 The relative composition of the TG and cholesterol in the lipoprotein classes may shift such that there are more TG-rich lipoproteins and a greater proportion of serum cholesterol is remnant cholesterol vs that seen in LDL-C particles.25,26 This may explain our finding of higher associated risk of adverse CV events among patients above non-HDL-C thresholds but below LDL-C thresholds for people with diabetes or CKD (but not for those without). People with CKD may also have additional nonlipoprotein-related causes of ASCVD.25
Apolipoprotein B (ApoB) is increasingly being emphasized in estimating CV risk. The National Lipid Association and European Society of Cardiology10,27 include consideration of ApoB in their treatment algorithm while the importance of ApoB is discussed in the 2019 American College of Cardiology/ American Heart Association primary prevention guideline.5 The 2021 CCS guidelines also include ApoB in their treatment algorithm and highlight that ApoB (or non-HDL-C) are generally preferable to LDL-C when interpreting lipid results.9 ApoB provides a more accurate assessment of atherogenic particles compared with LDL-C and is a better predictor of CV risk,2,28 and is correlated with non-HDL-C.29
We found that the highest associated risk was for the outcome of MI (Figure 1), whereas there was no association with all-cause mortality. This is broadly consistent with data on the benefits of statins in primary prevention, where the magnitude of benefit appears to be highest for vascular outcomes compared to all-cause mortality.30,31 This is particularly true for our older cohort, where competing risk of mortality is an issue.
Implication of findings
Contemporary guidelines have incorporated non-HDL-C thresholds into treatment algorithms.4,32 Our findings lend support to the thresholds proposed in Canadian guidelines. Lipid-lowering therapy decisions in primary prevention should be shared decisions based on individual CV risk (eg, Framingham Risk Score), the absolute chance of benefit and harm from therapy, and individual health goals and preferences. Repeat lipid testing might allow for identification of patients with residual risk for CV events despite initial statin therapy, and an opportunity for discussion of additional lipid-lowering therapy. This discussion will allow for shared decision-making to determine whether pursuing additional lipid lowering is consistent with a person’s health goals and treatment preferences. This discussion might be particularly important in patients at higher baseline risk of CV events, such as those with diabetes or CKD.
Study Limitations
We relied on health administrative databases in Ontario, which do not contain data on smoking status or blood pressure, thus we did not calculate estimated 10-year CV risk using popular risk scores (eg, Framingham Risk Scores). Furthermore, inflammatory pathways may be a risk factor for patients with CKD and we did not adjust for inflammatory markers (eg, C-reactive protein). We did not report or adjust for TGs. There may be differences between categories in makeup of non-HDL-C (eg, elevated TGs) which would be important to understand in future studies. Our study population included individuals ≥75 years of age where the benefits of statins for primary prevention are less certain (though guidelines acknowledge that initiation may be reasonable in well-functioning otherwise healthy older adults5,15). It is possible that our cohort included individuals where pursuing higher dose statins or lipid targets may not have been clinically appropriate. Furthermore, the relationship between LDL-C and CVD risk is less clear among older adults, with some studies finding LDL-C is not associated with CVD risk in this population.33 We did not assess statin use or lipid categories after index. Since residual risk from statin nonadherence across the study was not accounted for, differential rates of statin adherence may explain our findings. Furthermore, not all statin initiators had a repeat lipid test, which may have introduced selection bias. The lipid categories we used were based on the 2021 Canadian dyslipidemia guidelines, but our cohort was accrued from 2012 to 2019. The 2016 guidelines contained similar non-HDL-C and LDL-C thresholds and the 2012 guidelines included non-HDL-C as secondary thresholds. Regardless, our aim was to examine whether current guideline-directed thresholds for intensification are supported by real-world patterns of lipid-lowering therapy rather than analyzing practice patterns.
Conclusions
In this population-based cohort study of statin initiators, most people had a repeat lipid panel in the 1-year period after starting a statin. Among this group, the majority had LDL-C and non-HDL-C below guideline-directed thresholds for intensification but 20 to 30% did not. Having LDL-C and non-HDL-C above guideline-directed thresholds was associated with a higher rate of the composite of death, MI, stroke, or revascularization. Among people with diabetes or CKD, having an LDL-C below threshold but non-HDL-C above threshold for intensification was associated with a higher rate of adverse outcomes. Our findings support the existence of residual risk associated with incompletely controlled LDL-C or non-HDL-C as recommended in Canadian guidelines.
Perspectives.
COMPETENCY IN PATIENT CARE: Remaining above guideline-directed thresholds for LDL-C and non-HDL-C may be associated with residual risk of adverse CV outcomes. Clinicians should be particularly aware of non-HDL-C levels among persons with diabetes or CKD, as there may be residual risk from having non-HDL-C above guideline-directed thresholds even if LDL-C is below.
TRANSLATIONAL OUTLOOK 1: Residual risk associated with having LDL-C and/or non-HDL-C above threshold should be examined among adults younger than 65 to 75 years starting statins, where there is potential for longer follow-up and the potential benefit from lipid-lowering in primary prevention may be higher.
TRANSLATIONAL OUTLOOK 2: Further research should examine real-world residual risk associated with having ApoB above guideline-directed thresholds (while having LDL-C below threshold) after starting statins for primary prevention.
Funding support and author disclosures
Dr Udell is supported by a University of Toronto Department of Medicine Merit Award, the Peter Munk Cardiac Centre of the University Health Network, and the Department of Medicine of Women’s College Hospital and has received personal fees for consulting for or honoraria for lectures from Amgen, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Novartis, and Novo Nordisk. Dr Lee is the Ted Rogers Chair in Heart Function Outcomes, University Health Network, and University of Toronto. Dr Abdel-Qadir has received fees from the Canadian Vigour Centre for serving on the endpoint adjudication committee membership for the THEMIS (Ticagrelor vs Placebo in Patients With Type 2 Diabetes Mellitus) trial, which was funded by AstraZeneca. Dr Thompson is supported by a salary award from Michael Smith Health Research BC. Dr Odutayo is supported by the Canadian Institutes of Health Research (CIHR) Research Excellence, Diversity, and Independence (REDI) Early Career Transition Award, the Kidney Foundation of Canada, the Ted Rogers Centre for Heart Research, and the University of Toronto Black Research Network. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This study was also supported by a grant from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trial Multi-Year Grant (grant no. MYG 151211). This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from ©Canada Post Corporation and Statistics Canada. Parts of this material are based on data and/or information compiled and provided by the MOH, CIHI, and Ontario Health. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors thank IQVIA Solutions Canada Inc for use of their Drug Information File and the Toronto Community Health Profiles Partnership for providing access to the Ontario Marginalization Index.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental tables, please see the online version of this paper.
Supplementary data
References
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