Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Abstract

Summary Background Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

PCSK9 inhibitor therapy: A systematic review and meta‐analysis of metabolic and cardiovascular outcomes in patients with diabetes

“…Notably, the absence of hyperglycaemic effects with PCSK-9 inihibitors in clinical trials is at variance with the results of genetic studies, in which participants with alleles of PCSK-9 associated with lower LDL cholesterol have higher blood glucose levels and are at increased risk of diabetes. 15 As expected, the relative risk reduction in MACE is not significantly different in participants with and without diabetes, as previously reported in a small meta-analysis of patient-level data from phase III trials with alirocumab, 20 and in sub-group analyses of a cardiovascular outcome trial with evolocumab. 25 The finding is con- This result is in line with that observed with statin treatment.…”

“…Interestingly, another cholesterol‐lowering agent, ezetimibe, has not been associated with impairment of glucose metabolism; however, the number of available clinical trials with ezetimibe is relatively smaller than that with statins, possibly preventing the detection of minor differences in the incidence of diabetes. Notably, the absence of hyperglycaemic effects with PCSK‐9 inihibitors in clinical trials is at variance with the results of genetic studies, in which participants with alleles of PCSK‐9 associated with lower LDL cholesterol have higher blood glucose levels and are at increased risk of diabetes . On the other hand, in the large majority of available clinical trials, PCSK‐9 inhibitors were administered in the context of background therapy with statins, which could have masked the effect of the experimental drug on glucose metabolism.…”

“…Pro‐protein convertase subtilisin/kexin type 9 (PCSK‐9) inhibitors, which have been recently approved for treating hypercholesterolaemia in patients insufficiently controlled with other drugs, bring about a greater reduction in low‐density lipoprotein (LDL) cholesterol than statins . Interestingly, genetic variants of PCSK‐9 associated with lower LDL cholesterol are also associated with increased fasting glucose and higher risk of incident type 2 diabetes . As individuals with diabetes may represent a relevant proportion of those using PCSK‐9 inhibitors, it is important to know the specific effects of those drugs on glucose and lipid metabolism in diabetic patients.…”

“…[8][9][10][11][12][13][14] Interestingly, genetic variants of PCSK-9 associated with lower LDL cholesterol are also associated with increased fasting glucose and higher risk of incident type 2 diabetes. 15 As individuals with diabetes may represent a relevant proportion of those using PCSK-9 inhibitors, it is important to know the specific effects of those drugs on glucose and lipid metabolism in diabetic patients. The number of available trials with PCSK-9 inhibitors, some of which report separate analyses for subgroups with and without diabetes, allow for a reliable assessment of such effects.…”

Coronary artery disease in a rural population of Bangladesh: is dyslipidemia or adiposity a significant risk?

“…Additionally, it would have been better if we could include C-reactive protein [19,20], Vitamin D [21] and homocysteine level [22], which are considered CAD risk, directly or indirectly. Though not very evident, it is also important to explore whether genetic predisposition have any contribution to CAD [23,24].…”