Abstract
Background
Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for development of cardiovascular diseases. Based on available clinical data, we aimed to investigate the plasma lipid profile in the Greenlandic population, the proportion on cholesterol-lowering treatment and the adherence to local indications for cholesterol-lowering therapy.
Methods
This is an observational cross-sectional study of the adult (≥21 years) Greenlandic population with focus on clinically determined lipid levels from 2017 to early 2022. We investigated levels of dyslipidemia and assessed cholesterol-lowering medication usage in individuals with an indication according to current Greenlandic guidelines, which include a) LDL-C >5 mmol/l, b) diabetes, c) diagnosed atherosclerotic disease and 4) a SCORE2 >7.5%.
Results
In the adult Greenlandic population of 40,565 individuals a lipid profile was available in 13,895 with a mean LDL-C of 3.0 mmol/L and 976 (7%) had a LDL-C >5 mmol/l. One or more indications for cholesterol-lowering medication was present in 3988 individuals and a total of 5464 adult Greenlanders either fulfilled local criteria for statin therapy or received a statin (some without current indication) and among these, 2232 (41%) individuals received no statin.
Conclusion
These findings indicate that clinically significant dyslipidemia is common in the adult Greenlandic population and that the cardiovascular preventive potential of cholesterol-lowering therapy is currently underutilized.
Keywords: Plasma lipid, Cholesterol, Arctic health, Epidemiology, Statins
Highlights
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Clinically significant dyslipidemia is common in the adult Greenlandic population.
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Mean LDL-C among Greenlandic population was 3.0 mmol/L (SD 1.2).
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44% with an indication for a cholesterol-lowering medication received a statin.
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Cardiovascular preventive potential of cholesterol-lowering therapy is underutilized.
1. Introduction
Dyslipidemia is a well-established risk factor for development of cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) or non-HDL levels as a key factors [1]. High levels of LDL-C is a well-documented risk factor for atherosclerotic cardiovascular events, and numerous randomized controlled trials have shown that cholesterol-lowering medication reduces the risk of atherosclerotic cardiovascular events with statin therapy constituting the cornerstone in the pharmacological prevention and being effective as well as safe for both primary and secondary prevention [[2], [3], [4]].
The traditional Greenlandic diet contained marine mammals and fish and in the 1970–1990′s it was reported that the Greenlandic population had healthy plasma lipid profiles and low risk of developing cardiovascular diseases partially due a protective role against coronary artery disease and inflammation of this diet [[5], [6], [7], [8]]. However, the reported previously lower cardiovascular disease prevalence in Greenlanders has recently been questioned [9,10]. Worldwide the incidence of metabolic disorders is increasing due to changes in lifestyle and diet [11]. In Greenland with a population of 56,421 [12], the traditional lifestyle and diet have gradually changed to a more Western lifestyle with decreasing physical activity and a diet with a higher content of sugar and saturated fat [10]. This transition may have changed the lipid profile. Cardiovascular diseases have become a major public health issue in the Greenlandic population and additional risk factors are contributing, including a high prevalence of smokers, ageing of the population, and obesity [13].
Genetics play a major role in dyslipidemia and a LDL receptor (LDLR) missense variant (p.G137S) is common in the Greenlandic population with an allele frequency of 15.8% and an estimated effect size on LDL-C of 0.75 mmol/l per allele with a large impact on the population [14]. As the current lipid profile in the adult Greenlandic population is unknown we aimed to investigate the plasma lipid profiles in the adult Greenlandic population and estimate the proportion of Greenlanders with untreated high levels of LDL-C.
2. Methods
2.1. Study design and data
The present study is an observational cross-sectional study based on the adult Greenlandic population who have had determined the lipid profile on a routine clinical basis. Individual-level data was obtained from the electronic medical record (EMR) system Cambio COSMIC (Cambio, Sweden) utilized in the Greenlandic health care setting [15]. of the population. In Greenland, diseases are classified by either the International Classification of Diseases, 10th revision (ICD-10) or the International Classification of Primary Care 2nd edition (ICPC) and the validity of cardiovascular classifications in the EMR has been estimated to be 92–99% in the discharge register [16]. Data on demographic variables, smoking status and blood pressure was collected from the EMR. All active prescriptions are registered in the EMR and cholesterol-lowering medications were identified according to the drugs’ Anatomical Therapeutic Chemical (ATC) classification system. Noticeably, the healthcare system in Greenland is publicly financed, including medications. Atorvastatin is the first drug choice for cholesterol-lowering in Greenlandic. See Supplementary Table 1 on ICD-10 and ICPC classification codes, as well as ATC codes in Supplementary Table 2.
All blood test results for measurements of total-cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) from primary and secondary healthcare settings were included. Lipid-profiles, including LDL-C, were measured directly by enzymatic methods (Architect cSystems) and were obtained as a mixture of fasting and non-fasting results, as this has been deemed appropriate [17]. For individuals with multiple lipid measurements we utilized the last measured value in order to obtain the most current lipid status of the Greenlandic population.
2.2. Cholesterol-lowering medication and dyslipidemia
Current guidelines in Greenland specify four indications for cholesterol-lowering medication for individuals ≥21 years of age [18]. First, clinical atherosclerosis including previous myocardial infarction, unstable angina pectoris, stroke and peripheral vascular disease. Second, a LDL-C >5 mmol/l. Third, a Systematic COronary Risk Evaluation (SCORE2) [19,20] above 7.5%. Last, individuals with type II diabetes (and LDL-C 1.8–4.9 mmol/l). The latter two indications are only for individuals between 40 and 75 years of age. Individuals currently receiving a cholesterol-lowering medication, but for whom we were unable to identify any of the four indications were assumed to have a previous indication for cholesterol-lowering treatment. In general, dyslipidemia cut-off values associated with increased cardiovascular risk profile in Greenland have been set at LDL-C ≥3 mmol/l, HDL-cholesterol <1 mmol/l for males and <1.2 mmol/l for females, hypertriglyceridemia >2.0 mmol/l and total cholesterol >5 mmol/l [21].
2.3. SCORE and statistical analysis
We investigated statin treatment across age groups. European Society of Cardiology (ESC) has revised its recommended risk prediction algorithm, known as the Systematic COronary Risk Evaluation (SCORE) model in 2021 [22,23]. Two new algorithms, SCORE2 and SCORE2-OP (older persons, 70–89 years) emerged where SCORE2 is calculated using age, smoking status, systolic blood pressure, and non-HDL-cholesterol, whereas previous SCORE (2016) [24] and SCORE-OP (2015) [25] apply total cholesterol. SCORE system is categorized by countries with different risks and as a conservatory approach we chose to use the low-risk group as assigned to Denmark as Greenland is not mentioned in European Society of Cardiology categorization system. Furthermore, SCORE includes only fatal cardiovascular outcomes whereas SCORE2 estimates 10-year fatal and non-fatal cardiovascular risk. We included results from both SCORE and SCORE2. For combined values of blood pressure, age and cholesterol that would yield a SCORE2 >7.5% independent of smoking status, we chose to assign these patients for statin indication although smoking status was unknown.
Categorical variables are presented with frequencies and percentages, whereas continuous variables are presented as means with standard deviation (SD) or median with interquartile ranges (IQR). A sensitivity analysis was conducted where directly measured LDL-C values were adjusted for lipid-lowering treatment use by dividing the LDL-cholesterol by 0.8 corresponding to a 20% reduction in LDL-C level to achieve a non-treated mean LDL-C [26,27]. All statistical analyses were conducted using SAS 9.4 (Cary, NC, USA).
2.4. Approvals
The study was approved by the Ethics Committee for Medical Research in Greenland (reference number: KVUG 2016-09) and by the Agency for Health and Prevention in Greenland.
3. Results
3.1. Characteristics and dyslipidemia
Of the entire adult (≥21 years) population (N = 40,565) of Greenlanders a total of 13,959 (34.4%) adults had at least one lipid-profile between 2017 and February 2022. The adult population living in Greenland (N = 40,565) (Fig. 1), had a median age 45 years (IQR 32–58), 18,972 (46.8%) were females and the distribution between the five regions in Greenland and baseline characteristics of the total population is seen in Table 1.
Fig. 1.
Flowchart of the study population.
Table 1.
Characteristics of study population.
| Characteristic | Study population (N = 40,565)a |
|---|---|
| Median age, years (IQR) | 45 (32–58) |
| Female sex (%) | 18,972 (46.8) |
| Median body mass index, kg/m2 (IQR) | 29.0 (25.1–33.3) |
| Region | |
| Avannaa | 7804 (19.2) |
| Disko | 4384 (10.8) |
| Kujataa | 4602 (11.3) |
| Qeqqa | 6542 (16.1) |
| Sermersooq | 17,233 (42.5) |
| Currently smoking (%) | 4926 (49.0) |
| Blood pressure | |
| Median systolic, mmHg (IQR) | 132 (123–142) |
| Median diastolic, mmHg (IQR) | 81 (75–88) |
Not all patients had data on all variables; smoking status (n = 10,045), body mass index (n = 4980) and blood pressure (n = 10,647).
The mean lipid levels for the adult population were; total-cholesterol 4.9 mmol/L (SD 1.2), LDL-C 3.0 mmol/L (SD 1.2), HDL-C 1.3 mmol/L (SD 0.5) and triglycerides had a median concentration of 1.6 mmol/L (IQR 1.1–2.3). Thus, of the 13,959 patients, 79.4% fulfilled at least one criterion for dyslipidemia (see methods); high total-cholesterol (>5 mmol/l) was present in 46.8%, high LDL-C (≥3 mmol/l) in 45.8%, high triglycerides (>2 mmol/l) in 35.2% and low HDL-C (<1 mmol/l for males & <1.2 mmol/l for females) present in 29.7% (Table 2 and Fig. 2). In the sensitivity analysis of adjusting LDL-C for those already in statin treatment altered the mean LDL-C from 3.0 mmol/L (SD 1.2) to 3.1 mmol/L (SD 1.3).
Table 2.
Lipid profile.
| Totala | |||
|---|---|---|---|
| Yes (%) | No (%) | ||
| LDL-cholesterol ≥3 mmol/l | 6368 (45.8) | 7527 (54.2) | 13,895 |
| HDL-cholesterol <1 mmol/l for males & < 1.2 mmol/l for females | 3738 (29.7) | 8858 (70.3) | 12,596 |
| Triglycerides >2.0 mmol/l | 4906 (35.2) | 9041 (64.8) | 13,947 |
| Total cholesterol >5 mmol/l | 6527 (46.8) | 7419 (53.2) | 13,946 |
| Any type of dyslipidemia | 11,078 (79.4) | 2881 (20.6) | 13,959 |
Total of individuals with the respective lipid-profile blood sample investigated. Abbreviations: LDL = Low-density lipoprotein, HDL=High-density lipoprotein.
Fig. 2.
Distribution of lipid profiles in Greenland.
3.2. Patients with an indication for cholesterol-lowering medication
A total of 3988 individuals had a known indication for a cholesterol-lowering medication among 40,565 adults. The most common indication for a cholesterol-lowering medication was a high SCORE2 (N = 1491) followed by a diagnosis of atherosclerosis (N = 1204), diabetes (N = 987) and LDL-C >5 mmol/l (N = 976) yielding (Fig. 3). A total of 624 individuals had two or more indications for lipid-lowering therapy. Utilizing SCORE from 2016 instead of SCORE2 yielded only 213 individuals rather than 1491 with an indication for a statin. Noticeably, the true number of individuals with cholesterol-lowering indication for diabetes indication may be higher due to missing data for the LDL-C supplement criteria. Additionally, a substantial proportion of individuals had a SCORE2 and SCORE2-OP above 7,5%, but were not included as Greenlandic guidelines does not include individuals above 75 years.
Fig. 3.
Greenlanders receiving cholesterol medication according to indication
Noticeably, the true number of individuals with an indication for cholesterol-lowering medication due to the diabetes indication may be higher caused by missing data for the LDL-C supplement criteria. Furthermore, a large proportion of individuals were excluded for SCORE2 and SCORE2-OP as Greenlandic guidelines only include individuals <75 years.
1: Percentage of individuals receiving a statin by number of individuals fulfilling indication
2: Number of individuals receiving a statin
3: Number of individuals with an indication for a statin
4: Number of individuals with complete data for the given indication where especially SCORE requires gender, smoking status, blood pressure, age and cholesterol-level. A sign of (−) indicates that a figure for individuals with data was not obtainable (as those e.g. without a diagnosis cannot be classified as missing data).
3.3. Patients on cholesterol-lowering medication
Among the 3988 individuals with an indication for a cholesterol-lowering medication a total of 1756 (44%) received a statin. Combining individuals with an indication for cholesterol-lowering medication (n = 3988) and those on statin-therapy already (n = 3232) (assumedly previous indication fulfillment and potentially LDL-C reduction or SCORE2 risk adjustment) resulted in a total of 5464 individuals, i.e. patients on or fulfilling the criteria for lipid lowering therapy. Of the 5464 individuals with either an indication or currently on statin treatment, we found that 2232 (41%) individuals were not receiving a statin (Fig. 3 and Supplementary Table 4). The 3232 individuals receiving a statin represents 8% of the adult Greenlandic population (n = 40,565). Atorvastatin was the prescribed statin in 97% of patients in cholesterol lowering therapy. See Supplementary Table 5.
3.4. Time of measurement and seasonal variation
Within the last two years LDL-cholesterol blood samples were investigated at least once among 9494 (23,3%) Greenlanders (Supplementary Fig. 2). A substantial seasonal variation was found in average LDL-C levels (Supplementary Fig. 3). Average LDL-C by month was U-shaped with lowest LDL-C levels in July (LDL-C 2.5 mmol/l) and highest in December (LDL-C 3.6 mmol/l) with a p-value of <0.01 between the two extremes. Furthermore, we found that the majority of cholesterol measurements are performed during autumn.
4. Discussion
In this study of the adult Greenlandic population (N = 40,565) of which 13,895 individuals had data on LDL-C, we found that dyslipidemia is common among the adult Greenlandic population and a substantial proportion has an indication for a cholesterol-lowering medication. However, a considerable proportion of patients fulfilling the adjusted guideline criteria for interventions were not on cholesterol-lowering treatment, i.e. an underutilized cardiovascular preventative potential exists. Greenlandic guidelines state that atorvastatin is the first-line drug of choice, and our findings showed that physicians in Greenland adhere to this guideline.
We found that 79.4% (N = 11,078) of those with a lipid-profile fulfilled one or more criteria for dyslipidemia, i.e. LDL-C >3 mmol/l, triglycerides >2 mmol/l, HDL-C <1 mmol/l for males and <1.2 mmol/l for females or total-cholesterol >5 mmol/l. This figure cannot be extrapolated to the entire adult Greenlandic population due to selection bias of patients with a lipid-profile blood sample due to confounding by indication and while lipid-profiles data were missing not at random for two-thirds of the population we decided not to conduct multiple imputation. Nonetheless, it seems reasonable to assume that a considerable proportion of the around 27,000 adult Greenlanders without a lipid-profile also has a lipid-profile associated with increased risk of cardiovascular disease, particularly due to the common Arctic specific LDLR p.G137S missense variant [14]. Focus on dyslipidemia is highly relevant as high LDL-C was the 15th leading risk factor for death in 1990 and rose to 8th leading risk factor in 2019 [28].
We compared mean lipid levels in Greenland with various other countries from a study Global epidemiology of dyslipidaemias, published in Nature Review Cardiology in 2021 [28], however with potentially varying inclusion criteria across study populations. Mean LDL-C in Greenland was 3.0 mmol/L, as compared to 2.88 mmol/l in China and 2.8 mmol/L in Canada. A study published in 1992 on healthy adult Greenlandic Inuit (N = 133) found a mean LDL-C of 4.39 mmol/l [29], a study from 2000 of 259 randomly selected Greenlandic Inuit found a mean LDL-C of 3.24 mmol/l [8] and a study from 2004 found a mean LDL-C among Inuit (N = 1144) living in Greenland of 3.52 mmol/l [30], which are all higher than what we found in the present study. These figures may be due to selected populations in the previous studies. Also, the mean HDL-C was lower, the median triglyceride was higher and mean total cholesterol was higher in Greenlanders as compared with Chinese and Canadians. Regarding the circumpolar inhabitants there has been found high rates of coronary heart disease among Alaskan Eskimos and a population-based cohort from 2011 of 499 Alaska Eskimos above 45 years found an average LDL-C of approximately 3.2 mmol/L with around 12% of the population receiving cholesterol lowering medication, which is higher than the 8% among Greenlanders we found [31,32]. We found that 79.4% of Greenlanders fulfilled at least one criterion for dyslipidemia, as compared to 77.2% in Poland. Among statin treated patients (N = 1797) in the Baltic states, LDL-C was not at target level for 80.7% [33]. In Greenland target levels are not implemented according to guidelines.
Among individuals with an indication for cholesterol-lowering medication according to Greenlandic guidelines we found that the highest proportion of individuals in statin treatment in the group with an identified indication was due to atherosclerosis. These patients are often admitted to in-hospital treatment, which may result in higher adherence to guidelines due to longer hospitalization periods and attention. Opposite, among individuals with increased LDL-C, only 19% were on statin treatment. Figures suggest an underutilized cardiovascular preventive potential in the Greenlandic population, however this phenomenon is not specific for the Greenlandic population [34]. Life-long high levels of accumulated LDL-C is a greater risk and therefore undertreated young individuals with dyslipidemia may have the largest cardiovascular preventative potential and as seen in Supplementary Table 3 around 1.3% of adults below 50 years have a LDL-C>5 and therefore identifying these in individuals is important. Both American and European guidelines are centered on LDL-C lowering as a key strategy to reduce risk of a cardiovascular event, although these guidelines have some differences due to interpretation of the underlying evidence [35]. Greenlandic guidelines contain fewer indications compared to ESC/EAS guidelines (e.g. chronic kidney disease) [11] Statin usage worldwide has been on a markedly rise over the past decades and in 2016 approximately one in three Danes aged ≥70 years were taking a statin, which is comparable to the 31% (Supplementary Fig. 1) of individuals above ≥71 years taking a statin in Greenland [36,37]. Currently, statins are by far the most common cholesterol-lowering medication in Greenland as well as outside Greenland [38]. All prescriptive medications are free of charge in Greenland, but with a limited selection and standard care lipid-lowering therapy does not currently include PCSK9-inhibitors.
The seasonal dynamics or LDL-C found in the present study has likewise been reported by others, suggesting a global phenomenon [39]. We found the lowest LDL-C in July and highest in December with a difference that is larger than usually attributed to lifestyle factors. Albeit, organizational factors, e.g. routine controls for high risk individuals are primarily conducted outside summer holidays, may impact these findings. A review on the topic suggested potential mechanisms that included temperature, lifestyle alterations, blood volume and liver production activity with the clinical implication of potential diagnostic and treatment biases [39]. Considering the observed shift in lifestyle, including diet, in Greenland as well as the newly discovered common LDLR variant in the Greenlandic population, we believe further research into the circumstances of the current lipid status, genetic disposition, treatment effect and outcomes that affects citizens of Greenland is justified.
Findings presented in this study are to be interpreted with several limitations. First, the study did not include data on statin adherence or dosage. Secondly, some patients are tertiary referrals to treatment outside Greenland, primarily Denmark, and cholesterol levels were not obtained from these visits. Thirdly, missing data may underestimate the number of individuals with an indication for a cholesterol-lowering medication. Lastly, generalizability of our data to the overall Greenlandic population should be interpreted with confounding by indication in mind. A major strength of the present study is the inclusion of clinically obtained information from the entire adult Greenlandic population with access to high-quality data providing prescriptions, laboratory results, demographic variables and diagnoses.
In conclusion, dyslipidemia is common among the adult Greenlandic population at comparable levels to Westernized countries. A substantial proportion of Greenlanders have an indication for a cholesterol-lowering medication and current levels of cholesterol-lowering medication suggest an underutilized cardiovascular preventative potential according to Greenlandic guidelines.
Funding
This study received a grant from the Novo Nordisk Foundation: NNF20SA0064190.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Henning Bundgaard reports receiving lecture fees from MSD, BMS, Amgen and Sanofi. Marit E Jørgensen reports receiving research grants from AMGEN, Astra Zeneca, Boehringer Ingelheim, Novo Nordisk and Sanofi Aventis and holds shares in Novo Nordisk A/S. The remaining authors report no conflicts of interest.
Acknowledgements
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.athplu.2022.12.003.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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