Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel ...therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol-related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol-decreasing gene scores and allele numbers associated with up to -13 and -20% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38-1.52) and 1.77 (1.61-1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75-1.09) and 0.93 (0.78-1.11) for HDL cholesterol-decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32-1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.
Background:
Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear.
...Methods:
We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis.
Results:
Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11–2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70–2.62) (Pcomparison = 0.03).
Conclusion:
Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.
To compare clinical features of patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) with those of patients with similar body mass index (BMI) but no HF and to ...examine the association between degree of obesity and risk for hospitalizations.
This was a retrospective analysis of 22,750 adults from a large US electronic health care data set (January 1, 2012, through July 31, 2019), including 4975 with HFpEF. Baseline characteristics were compared between patients with HFpEF and a control group matched on BMI, age, sex, and year of BMI record. Risk of first hospitalization was analyzed in the HFpEF sample with negative binomial and Cox proportional hazards models, adjusted for baseline comorbidities.
Compared with controls without HF matched on BMI, age, sex, and year of BMI record, patients with HFpEF displayed worse kidney function, greater estimated plasma volume, and more cardiovascular comorbidities. Within the HFpEF cohort, patients with higher degree of obesity were younger and had fewer concomitant cardiovascular comorbidities than those with lower degree of obesity. The mean number of HF-related hospitalizations increased with higher degree of obesity (9.6 to 15.7/100 patient-years; P=.002), but higher degree of obesity was not associated with increased risk of non–HF-related hospitalizations.
Among persons with obesity, increasing cardiorenal dysfunction and volume overload differentiate those with HFpEF. Among persons with established HFpEF, those with higher degree of obesity are younger and have fewer cardiovascular comorbidities but display a unique increased risk of HF-related hospitalizations, even as risk for other hospitalizations is not different.
Context: Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart ...disease (IHD).
Objective: We tested whether common genetic variation in the apolipoprotein A1 gene (APOA1) contributes to apoA-I and HDL cholesterol levels and risk of IHD in the general population.
Design: We resequenced the regulatory and coding regions of APOA1 in 190 individuals from the Copenhagen City Heart Study with the lowest 1% (n = 95) and highest 1% (n = 95) apoA-I levels. Two single-nucleotide polymorphisms (SNPs) were subsequently genotyped in the Copenhagen City Heart Study (n = 10,273) and in 2361 cases with IHD (the Copenhagen Ischemic Heart Disease Study).
Results: In total, 13 genetic variants were identified. Three SNPs, g.−560A→C, g.-151C→T, and *181A→G, determined a haplotype that differed between high and low apoA-I groups (6 vs. 1%, P = 0.002). Genotype combinations of two SNPs, the g.−560A→C (tagging the g.−560A→C/g.−151C→T/*181A→G haplotype) and g.−310G→A (situated near a potential functional promoter site), were associated with increases in apoA-I and HDL cholesterol levels of up to 6.6 and 8.5%, respectively, resulting in theoretically predicted reductions in risk of 9 and 8% for IHD and 14 and 12% for myocardial infarction (MI). Despite this, these same genotype combinations were not associated with decreased risk of IHD or MI.
Conclusion: Common genetic variation in APOA1 associated with increased apoA-I and HDL cholesterol levels did not associate with decreased risk of IHD or MI.
Common genetic variation in APOA1 associated with higher apoA-I and HDL cholesterol levels do not associate with decreased risk of IHD.
Objective
Real‐world clinical effectiveness of liraglutide 3.0 mg, in combination with diet and exercise, was investigated 4 and 6 months post initiation. Changes in absolute and percent body weight ...were examined from baseline.
Methods
A cohort of liraglutide 3.0 mg initiators in 2015 and 2016 was identified from six Canadian weight‐management clinics. Post initiation values at 4 and 6 months were compared with baseline values using a paired t test.
Results
The full cohort consisted of 311 participants, with 210 in the ≥ 4‐month persistence group and 167 in the ≥ 6‐month persistence group. Average baseline BMI was 40.7 kg/m2, and weight was 114.8 kg. There was a significant change in body weight 6 and 4 months after initiation of treatment in persistent subjects (≥ 6‐month: −8.0 kg, P < 0.001; ≥ 4‐month: −7.0 kg, P < 0.001) and All Subjects, regardless of persistence (−7.3 kg; P < 0.001). Percentage change in body weight from baseline was −7.1% in the ≥ 6‐month group and −6.3% in the ≥ 4‐month group, and All Subjects lost 6.5% body weight. Of participants in the ≥ 6‐month group, 64.10% and 34.5% lost ≥ 5% and > 10% body weight, respectively.
Conclusions
In a real‐world setting, liraglutide 3.0 mg, when combined with diet and exercise, was associated with clinically meaningful weight loss.
Objective
Obesity rates in the United Kingdom are some of the highest in Western Europe, with considerable clinical and societal impacts. Obesity is associated with type 2 diabetes (T2D), ...osteoarthritis, cardiovascular disease, and increased mortality; however, relatively few studies have examined the occurrence of multiple obesity‐related outcomes in the same patient population. This study was designed to examine the associations between body mass index (BMI) and a broad range of obesity‐related conditions in the same large cohort from a UK‐representative primary care database.
Methods
Demographic data and diagnosis codes were extracted from the Clinical Practice Research Datalink GOLD database in January 2019. Adults registered for ≥ 3 years were grouped by BMI, with BMI 18.5–24.9 kg/m2 as reference group. Associations between BMI and 12 obesity‐related outcomes were estimated using Cox proportional hazard models, adjusted for age, sex, and smoking.
Results
More than 2.9 million individuals were included in the analyses and were followed up for occurrence of relevant outcomes for a median of 11.4 years during the study period. Generally, there was a stepwise increase in risk of all outcomes with higher BMI. Individuals with BMI 40.0–45.0 kg/m2 were at particularly high risk of sleep apnea (hazard ratio 95% confidence interval vs. reference group: 19.8 18.9–20.8), T2D (12.4 12.1–12.7), heart failure (3.46 3.35–3.57), and hypertension (3.21 3.15–3.26).
Conclusions
This study substantiates evidence linking higher BMI to higher risk of a range of serious health conditions, in a large, representative UK cohort. By focusing on obesity‐related conditions, this demonstrates the wider clinical impact and the healthcare burden of obesity, and highlights the vital importance of management, treatment approaches, and public health programs to mitigate the impact of this disease.
Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and ...population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09-2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0-1(st) percentile) and 21% (screening 0-20(th) percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI.
Summary
Objective
Liraglutide 3.0 mg is associated with clinically significant weight loss in clinical trials, but real‐world data are lacking. In this analysis, weight loss and persistence outcomes ...with liraglutide 3.0 mg were assessed across obesity classes, in a real‐world clinical setting.
Methods
Secondary analysis of an observational, retrospective study of liraglutide 3.0 mg for weight management (as adjunct to diet and exercise) at six Wharton Medical Clinics in Canada. Patients were categorized by body mass index (BMI, kg/m2) into obesity class I (BMI 30–34.9); class II (BMI 35–39.9); and class III (BMI ≥40). Change in weight, categorical weight loss, time to maintenance dose (defined as the time to reach the full liraglutide 3.0 mg maintenance dose) and persistence were assessed for each class and for differences between classes.
Results
Of 308 patients, 70 (22.7%) had obesity class I, 83 (26.9%) obesity class II and 155 (50.3%) obesity class III. Similar percentage change in weight was observed between obesity classes (mean standard deviation, SD: −7.0% 6.0, −6.6% 6.0 and −6.1% 5.0, respectively; p = .640), and similar proportions achieved ≥5% weight loss (60.4%, 62.0% and 55.3%, respectively; p = .717) at 6 months. Mean time to maintenance dose (SD) was 64.2 (56.4) d, 76.4 (56.3) d and 71.4 (54.5) d for obesity classes I, II and III, respectively (p = .509). Persistence with medication was also similar between obesity classes (p = .358).
Conclusions
These findings suggest that real‐world treatment with liraglutide 3.0 mg, regardless of obesity class, is associated with similar clinically significant weight loss, time to maintenance dose and medication persistence.
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