Summary After the introduction of statins, clinical emphasis first focussed on LDL cholesterol-lowering, then on the potential for raising HDL cholesterol, with less focus on lowering triglycerides. ...However, the understanding from genetic studies and negative results from randomised trials that low HDL cholesterol might not cause cardiovascular disease as originally thought has now generated renewed interest in raised concentrations of triglycerides. This renewed interest has also been driven by epidemiological and genetic evidence supporting raised triglycerides, remnant cholesterol, or triglyceride-rich lipoproteins as an additional cause of cardiovascular disease and all-cause mortality. Triglycerides can be measured in the non-fasting or fasting states, with concentrations of 2–10 mmol/L conferring increased risk of cardiovascular disease, and concentrations greater than 10 mmol/L conferring increased risk of acute pancreatitis and possibly cardiovascular disease. Although randomised trials showing cardiovascular benefit of triglyceride reduction are scarce, new triglyceride-lowering drugs are being developed, and large-scale trials have been initiated that will hopefully provide conclusive evidence as to whether lowering triglycerides reduces the risk of cardiovascular disease.
Summary Background Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients ...given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. Methods In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio HR 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. Interpretation For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. Funding AstraZeneca.
The reason why lipoprotein(a) concentrations are raised in individuals with clinical familial hypercholesterolaemia is unclear. We tested the hypotheses that high lipoprotein(a) cholesterol and LPA ...risk genotypes are a possible cause of clinical familial hypercholesterolaemia, and that individuals with both high lipoprotein(a) concentrations and clinical familial hypercholesterolaemia have the highest risk of myocardial infarction.
We did a prospective cohort study that included data from 46 200 individuals from the Copenhagen General Population Study who had lipoprotein(a) measurements and were genotyped for common familial hypercholesterolaemia mutations. Individuals receiving cholesterol-lowering drugs had their concentrations of LDL and total cholesterol multiplied by 1·43, corresponding to an estimated 30% reduction in LDL cholesterol from the treatment. In lipoprotein(a) cholesterol-adjusted analyses, total cholesterol and LDL cholesterol were adjusted for the lipoprotein(a) cholesterol content by subtracting 30% of the individuals' lipoprotein(a) total mass before total and LDL cholesterol were used for diagnosis of clinical familial hypercholesterolaemia. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria to clinically diagnose familial hypercholesterolaemia. Cox proportional hazard regression calculated hazard ratios (95% CI) of myocardial infarction.
Using unadjusted LDL cholesterol, mean lipoprotein(a) concentrations were 23 mg/dL in individuals unlikely to have familial hypercholesterolaemia, 32 mg/dL in those with possible familial hypercholesterolaemia, and 35 mg/dL in those with probable or definite familial hypercholesterolaemia (ptrend<0·0001). However, when adjusting LDL cholesterol for lipoprotein(a) cholesterol content the corresponding values were 24 mg/dL for individuals unlikely to have familial hypercholesterolaemia, 22 mg/dL for those with possible familial hypercholesterolaemia, and 21 mg/dL for those with probable or definite familial hypercholesterolaemia (ptrend=0·46). High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia and LPA risk genotypes were more frequent in clinical familial hypercholesterolaemia, whereas lipoprotein(a) concentrations were similar in those with and without familial hypercholesterolaemia mutations. The hazard ratios (HRs) for myocardial infarction compared with individuals unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less were 1·4 (95% CI 1·1-1·7) in those unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentrations of more than 50 mg/dL, 3·2 (2·5-4·1) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less, and 5·3 (3·6-7·6) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of more than 50 mg/dL. In analyses using Simon Broome or MEDPED criteria, results were similar to those using DLCN criteria to diagnose clinical familial hypercholesterolaemia.
High lipoprotein(a) concentrations and corresponding LPA risk genotypes represent novel risk factors for clinical familial hypercholesterolaemia. Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction.
Danish Heart Association and IMK General Fund, Denmark.
COPD can be diagnosed early using spirometry, but spirometry use is only recommended in symptomatic smokers, even though early stages of COPD can be asymptomatic. We investigated the prognosis of ...individuals with asymptomatic and symptomatic, undiagnosed COPD in the general population in Denmark.
In this prospective cohort study, we analysed data from 95 288 individuals aged 20-100 years from the Copenhagen General Population Study. 32 518 (34%) of these individuals were regarded as being at high risk for COPD (defined as individuals aged 40 years or older, with cumulative tobacco consumption of ten pack-years or higher, and without self-reported or a previous hospital contact for asthma). COPD was defined as FEV
/forced vital capacity (FVC) of less than 70% and less than the lower limit of normal, and FEV
of less than 80% of the predicted normal value. Individuals were considered undiagnosed if neither a previous COPD hospital contact, nor medical treatment for COPD, was registered. We obtained information on exacerbations and pneumonia from the National Danish Patient Registry and vital status from the National Danish Civil Registration System, and cause of death from the National Danish Causes of Death Registry. We used Cox proportional hazard models to assess risk of exacerbations, pneumonia, deaths due to respiratory causes, and deaths from all causes from 2003 to 2014.
Between Nov 26, 2003, and July 10, 2013, 95 288 individuals were screened and 32 518 (34%) were at high risk of having COPD. 3699 (11%) of these participants met the COPD criteria and 2903 (78%) were undiagnosed, of whom 2052 (71%) were symptomatic. During a median follow-up of 6·1 years (IQR 4·9), we recorded 800 exacerbations, 2038 cases of pneumonia, and 2789 deaths in the 32 518 individuals at high risk of having COPD, including 152 deaths due to respiratory disease. Compared with individuals without COPD, the age and sex adjusted hazard ratio (HR) was 5·0 (95% CI 2·8-8·9) for exacerbations, 1·7 (1·3-2·2) for pneumonia, 0·7 (0·2-3·0) for death from respiratory causes, and 1·3 (1·1-1·6) for death from all causes in individuals with undiagnosed, asymptomatic COPD. Corresponding HRs were 15·5 (11·0-21·8) for exacerbations, 2·8 (2·4-3·3) for pneumonia, 4·3 (2·8-6·7) for death from respiratory causes, and 2·0 (1·8-2·3) for death from all causes in individuals with undiagnosed, symptomatic COPD.
Individuals with undiagnosed, symptomatic COPD had an increased risk of exacerbations, pneumonia, and death. Individuals with undiagnosed, asymptomatic COPD had an increased risk of exacerbations and pneumonia. These findings suggest that better initiatives for early diagnosis and treatment of COPD are needed.
The Danish Lung Association, the Danish Cancer Society, Herlev and Gentofte Hospital, Copenhagen University Hospital, and University of Copenhagen.
Summary Background HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains ...when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Methods Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3·37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings For 17 802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0·0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2·80 mmol/L IQR 2·43–3·24), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio HR 0·54, 95% CI 0·35–0·83, p=0·0039) and on-treatment (0·55, 0·35–0·87, p=0·0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1·42 mmol/L IQR 1·14–1·86), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1·12, 0·62–2·03, p=0·82) or on-treatment (1·03, 0·57–1·87, p=0·97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group. Interpretation Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol. Funding AstraZeneca.
A substantial proportion of patients with chronic obstructive pulmonary disease (COPD) have never smoked. We tested the hypothesis that, in individuals with COPD, never smokers have different ...characteristics and less severe outcomes of the disease than smokers do.
We included individuals from the Copenhagen General Population Study, a prospective population study. We identified individuals with COPD spirometrically; that is, as the ratio between forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) under the lower limit of normal (LLN), excluding individuals with self-reported asthma. We examined general characteristics, symptoms, disease severity, and levels of inflammatory biomarkers and α1-antitrypsin at baseline. We assessed risk of lung-related hospital admissions, cardiovascular comorbidities, and all-cause mortality during a median follow-up of 4 years (IQR 2.5-5.6).
Between Nov 26, 2003, and July 29, 2010, 68,501 participants from the Copenhagen General Population Study had lung function measurements and complete information on smoking habits available. Of those, we identified 6623 with COPD and no asthma. Of these, 1476 (22%) were never smokers, 2696 (41%) former smokers, and 2451 (37%) current smokers. For comparison we included 24,529 never smokers without COPD. Never smokers with COPD had different clinical characteristics, fewer symptoms, milder disease, and lower levels of inflammatory biomarkers than did current and former smokers with COPD. During follow-up, HRs for hospital admission due to COPD were 8.6 (95% CI 5.3-14) in never smokers, 30 (22-41) in former smokers, and 43 (32-59) in current smokers compared with never smokers without COPD. HRs for hospital admission due to pneumonia were 1.9 (1.4-2.6) in never smokers, 2.8 (2.3-3.4) in former smokers, and 3.4 (2.9-4.2) in current smokers. For hospital admission due to lung cancer, HRs were 11 (5.7-23) in former smokers and 18 (9.2-35) in current smokers, whereas no cases were noted in never smokers. Furthermore, risk of cardiovascular comorbidities and all-cause mortality was increased in former and current smokers but not in never smokers with COPD.
Compared with current and former smokers, never smokers with COPD had different characteristics and milder disease, limited to the lungs. However, morbidity due to lung-related hospital admissions was nonetheless substantial in never smokers with COPD.
Herlev Hospital, Copenhagen University Hospital, Copenhagen County Foundation, and University of Copenhagen.
Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, ...and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.
Low plasma 25-hydroxyvitamin D (25OHD) concentration and high BMI have been associated with increased risk of diabetes. We tested the hypotheses that genetic variants associated with low ...concentrations of 25(OH)D are associated with diabetes, and that the effect on diabetes of genetic variants associated with high BMI is partly mediated through reduced plasma 25(OH)D concentration.
In this mendelian randomisation study, we genotyped 96 423 white Danes aged 20-100 years from three studies. 5037 of these participants had type 2 diabetes. All individuals were surveyed for diabetes from 1977 to 2011. 31 040 participants had their plasma 25(OH)D concentration measured and 90 169 had their BMI measured. We assessed the effects of genetic variation in DHCR7 (related to endogenous production) and CYP2R1 (related to liver conversion) on plasma 25(OH)D concentration, and the effects of variation in FTO, MCR4, and TMEM18 on BMI. We then assessed the effect of genetic variation in these genes on risk of type 2 diabetes, and the association of measured plasma 25(OH)D concentration and BMI with risk of type 2 diabetes. We did a mediation analysis to assess how much of the effect of BMI genotype on risk of diabetes was mediated through plasma 25(OH)D concentration.
The odds ratios for type 2 diabetes for participants who had a 20 nmol/L reduction in plasma 25(OH)D concentration as determined by genetics were 1·51 (95% CI 0·98-2·33) for DHCR7 and 1·02 (0·75-1·37) for CYP2R1. The DHCR7 allele score was significantly associated with increased risk of type 2 diabetes (p for trend=0·04), whereas the allele score for CYP2R1 was not. For participants who had a measured 20 nmol/L reduction in plasma 25(OH)D concentration, the adjusted odds ratio for type 2 diabetes was 1·16 (1·08-1·25). For participants who had a 10 kg/m(2) increase in BMI as determined by genetics, the odds ratio for type 2 diabetes was 19·4 (6·4-59·1); this was associated with an 11·1 nmol/L (2·6-19·6) lower plasma 25(OH)D concentration. For a 10 kg/m(2) increase in measured BMI, the adjusted odds ratio for type 2 diabetes was 4·33 (3·70-5·07); this was associated with a 9·1 nmol/L (8·4-9·7) lower plasma 25(OH)D concentration. Mediation analysis showed that 3% (1-5) of the effect of BMI on risk of type 2 diabetes was mediated through lowered plasma 25(OH)D concentrations.
Genetic variants associated with low plasma 25(OH)D concentrations are associated with type 2 diabetes and low plasma 25(OH)D concentrations might be a modest mediator between obesity and increased risk of diabetes. Genetic variants associated with endogenous production of 25(OH)D might partially explain this increased risk; however, as findings for DHCR7 were not statistically significant, our results require independent confirmation.
Danish Heart Foundation, Copenhagen University Hospital.
Low concentrations of lipoprotein(a) in plasma are associated with increased risk of type 2 diabetes, but whether this association is causal is unclear. Variations in the LPA gene affect ...lipoprotein(a) isoform size and concentrations in plasma. We therefore did a Mendelian randomisation study to investigate whether large isoform size, low concentrations in plasma, or both, are causally associated with type 2 diabetes.
We assessed data for adults from the Danish general population enrolled in the Copenhagen City Heart Study and the Copenhagen General Population Study, with and without type 2 diabetes. Eligible participants had data for lipoprotein(a) concentrations in plasma, LPA kringle IV type 2 (KIV-2) sums of repeats (affecting both isoform size and plasma concentrations), and carrier status for the LPA single-nucleotide polymorphism rs10455872 (mainly affecting concentrations in plasma).
77,901 individuals had lipoprotein(a) data, of whom 28,567 (36·7%) had all three measurements. Low concentrations of lipoprotein(a) in plasma were associated with risk of type 2 diabetes, with adjusted odds ratios of 1·26 (1·09-1·45), 1·17 (1·01-1·36), 1·04 (0·90-1·21), and 1·05 (95% CI 0·90-1·22), respectively, for quintiles 1-4, compared with quintile 5 concentrations. High KIV-2 sums of repeats were associated with risk of type 2 diabetes (adjusted odds ratio 1·16, 95% CI 1·05-1·28) for KIV-2 quintile 5 versus quintiles 1-4 combined. Being a carrier of rs10455872 did not affect risk of type 2 diabetes. For a halving of lipoprotein(a) concentrations, the instrumental variable estimate of the causal odds ratio for type 2 diabetes was 1·15 (95% CI 1·05-1·27) for KIV-2 sum of repeats and 0·99 (0·95-1·03) for rs10455872 genotype.
Low lipoprotein(a) concentrations alone seem not to be causally associated with type 2 diabetes, but a causal association for large lipoprotein(a) isoform size cannot be excluded.
Danish Heart Foundation, Danish Council for Independent Research-Medical Sciences, IMK Almene Fund, and Johan and Lise Boserup's Fund.
The role of statins in the development of microvascular disease in patients with diabetes is unknown. We tested the hypothesis that statin use increases the risk of diabetic retinopathy, diabetic ...neuropathy, diabetic nephropathy, and gangrene of the foot in individuals with diabetes.
We identified all patients living in Denmark who were aged 40 years or older and were diagnosed with incident diabetes between Jan 1, 1996, and Dec 31, 2009. We obtained patients' data from the Danish Patient Registry and information on drug use from the Danish Registry of Medicinal Product Statistics. We randomly selected 15,679 individuals from the database who had used statins regularly until their diagnosis of diabetes (statin users) and matched them in a 1:3 ratio with 47,037 individuals who had never used statins before diagnosis (non-statin users). Our primary outcome was to compare the cumulative incidence of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or gangrene of the foot in statin users versus non-statin users. We analysed data with Cox regression models, adjusted for covariates including sex, age at diabetes diagnosis, and method of diabetes diagnosis. To address potential biases between statin users and non-statin users, we made adjustments to our analysis with a propensity score and with other factors. Median follow-up was 2·7 years (range 0-13).
During 215,725 person-years of follow-up, 2866 patients developed diabetic retinopathy, 1406 developed diabetic neuropathy, 1248 developed diabetic nephropathy, and 2392 developed gangrene of the foot. Compared with non-statin users, statin users had a lower cumulative incidence of diabetic retinopathy (hazard ratio 0·60, 95% CI 0·54-0·66; p<0·0001), diabetic neuropathy (0·66, 0·57-0·75; p<0·0001), and gangrene of the foot (0·88, 0·80-0·97; p=0·010), but not diabetic nephropathy (0·97, 0·85-1·10; p=0·62). These results were similar after adjusting for the competing risk of death, after matching for a propensity score, after adjusting for visits to a family doctor, and by stratification on covariates. The corresponding multivariable adjusted hazard ratio for risk of diabetes in the total population was 1·17 (95% CI 1·14-1·21; p<0·0001).
Use of statins before diagnosis of incident diabetes was not associated with an increased risk of microvascular disease. Whether statins are protective against some forms of microvascular disease-a possibility raised by these data-will need to be addressed in other studies similar to ours, in mendelian randomisation studies, and preferably in randomised controlled trials.
Herlev Hospital, Copenhagen University Hospital.
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