Tuesday June 27 Late-Breaking Session

Increased non-fasting glucose levels are causal in ischemic heart disease

Marianne Benn, Copenhagen University Hospital, Herlev Hospital, Copenhagen, Denmark

This Mendelian randomization study concluded that elevated nonfasting glucose levels show a causal association between variants in GCK(rs4607517), G6PC2(rs560887), ADCY5(rs11708067), DGKB(rs2191349), and ADRA2A(rs10885122) and ischemic heart disease. All of these variants are associated with elevated fasting glucose levels in genome-wide association studies. This study included data from 80,522 white persons from Copenhagen, Denmark of whom 13,824 developed ischaemic disease.

The risk of ischemic heart disease increased stepwise with increasing nonfasting glucose levels, with the hazard ratio (for individuals with nonfasting glucose levels ≥11 mmol/L(≥198mg/dL) versus < 5 mmol/L(< 90mg/dL) of 7.3(95%CI: 4.5-12.1) adjusted for age and gender and 2.6(1.4-4.8) adjusted multifactorially. Increasing number of glucose increasing alleles was associated with increasing nonfasting glucose levels, and increased risk of IHD. For a 1 mmol/L(18mg/dL) increase in nonfasting glucose levels due to these variants, the estimated causal odds ratio for ischemic heart disease was 1.24(1.01-1.524). The corresponding observed hazard ratio using Cox regression was 1.18(1.15-1.22).

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

The European Atherosclerosis Society Consensus Panel

Chapman MJ, Ginsberg HN (Co-chairs), Amarenco P, Andreotti F, Boren J, Catapano AL, Descamps O, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray K, Reiner Z, Taskinen M R, Tokgozoglu L, Tybjærg-Hansen A, Watts GF

The EAS Consensus Panel has published new guidance on the management of atheorgenic dyslipidemia, i.e. elevated triglycerides with or without low HDL cholesterol. The Consensus Panel paper highlights the high risk associated with atherogenic dyslipidemia. The paper was published in the European Heart Journal April 29, 2011,¹ and discussed today.

The findings of the Consensus Paper are further supported by recent evidence the PROCAM study (upublished data, personal communication), which showed high coronary risk associated with the combination of low HDL cholesterol and elevated triglycerides in a cohort of diabetes patients. Additionally the Framingham Heart Study,² in 2,910 non-diabetic individuals followed-up for an average of 14 years, showed that that the presence of insulin resistance together with the lowest values of HDL cholesterol or the highest values of triglycerides was associated with increased coronary risk (p<0.001).

The guidance is based on comprehensive appraisal of current evidence. The EAS emphasises that lifestyle, including exercise and a healthy diet, is a fundamental first step in addressing elevated triglycerides (≥1.7 mmol/L or 150 mg/dL) and/or a low HDL cholesterol concentration (<1.0 mmol/L or 40 mg/dL) in high-risk patients at LDL cholesterol goal. The guidance reaffirms the fundamental role of lifestyle as key first step in managing these high risk patients. The Panel stresses that their recommendations are based on expert consensus from available evidence, and are consistent with current guidelines on dyslipidemia.

1. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, Descamps OL, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen M-R, Tokgozoglu L, Tybjærg-Hansen A, Watts GF for the European Atherosclerosis Society Consensus Panel. Published on-line European Heart Journal April 29, 2011. http://eurheartj.oxfordjournals.org/content/early/2011/04/29/eurheartj.ehr112.full.pdf+html

2. Robins SJ, Lyass A, Zachariah JP et al. Insulin resistance and the relationship of a dyslipidemia to coronary heart disease. The Framingham Heart Study. Arterioscler Thromb Vasc Biol 2011;31:doi:10.1161/atvbaha.110.219055

Plant Sterols and cardiovascular disease: A systematic review and meta-analysis

Winfried März, Synlab Center of Laboratory Diagnostics Heidelberg, Germany

Results from this systematic meta-analysis including data from 17 studies including 11,182 subjects did not show any evidence for an association between serum levels of plant sterols and risk of cardiovascular disease.

A systematic literature review using the databases MEDLINE, EMBASE and COCHRANE was conducted to investigate this association. Studies published by April 2010 reporting serum concentrations of the exposures of interest and a) risk ratios with respect to CVD endpoints or b) summary statistics of concentrations in CVD cases and controls separately were included. The design, study population, summary statistics of concentrations, risk ratios (RR) of CVD related endpoints, statistical methods and list of confounding variables used in multivariate modelling were extracted from each study. RRs were transformed to contrast the upper vs. the lower tertile of the distribution of exposure serum concentrations with respect to the endpoint “all CVD events pooled”. For studies that reported serum levels of CVD cases and controls separately standardized mean differences (SMDs) and standard errors were calculated. The RR (95% CI) was 1.17 (0.97 to 1.42) for campesterol and 0.90 (0.75 to 0.90) for sitosterol.

Alipogene tiparvovec gene therapy significantly reduces the risk of pancreatitis in lipoprotein lipase deficient patients

Amsterdam Molecular Therapeutics (AMT) B.V., the Netherlands

Results from this case-control study showed that one-time alipogene tiparvovec was efficacious and resulted in statistically and clinically significant reduction in risk of the combined endpoint of severe acute abdominal pain, or probable or definite pancreatitis in patients with lipoprotein lipase deficiency (LPLD). No patients died during the study.

Twenty patients were enrolled, of whom 17 had previously been administered alipogene tiparvovec. Historical data for all hospital presentations due to abdominal pain were collected. Data collection and pancreatitis definition were according to modified Atlanta Diagnostic Criteria for acute pancreatitis, to allow for incomplete historical data. Blinded event assessment was done by an expert adjudication committee. Statistical analysis to model the hazard of pancreatitis pre/post therapy was executed using a Cox regression gap time model.

There was a statistically significant (p=0.0434) reduction in the risk of acute pancreatitis for the period from the first pancreatitis event to administration was compared with the post-therapy period (median = 2.9 years). The hazard ratio indicated a 63% reduction in risk of acute pancreatitis after alipogene tiparvovec (95% CI 0.142-0.971).