Objectives To evaluate (1) the inter-individual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) levels achieved with statin therapy, (2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy, and (3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and CVD risk. Background Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease (CVD) risk is not well documented. Methods Meta-analysis of individual patient data from 8 randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Results Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large inter-individual variability in the reductions of LDL-C, non-HDL-C and apoB achieved with a fixed statin dose. Over 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target below 70 mg/dL. Compared to patients who achieved an LDL-C > 175 mg/dL, those who reached an LDL-C 75-100 mg/dL, 50-75 mg/dL and < 50 mg/dL had adjusted hazard ratios for major cardiovascular events of 0.56 (95%CI 0.46-0.67), 0.51 (95%CI 0.42-0,62) and 0.44 (95%CI 0.35-0.55), respectively. Similar associations were observed for non-HDL-C and apoB. Conclusions The reduction of LDL-C, non-HDL-C and apoB levels achieved with statin therapy displays large inter-individual variation. Among trial participants treated with high-dose statin therapy, over 40% do not reach an LDL-C target <70 mg/dL. Patients who achieve very low LDL-C levels have a lower risk of major cardiovascular events than those achieving moderately low levels.

Aims/hypothesisWomen with gestational diabetes mellitus (GDM) are at risk of developing type 2 diabetes, but individualised risk estimates are unknown. We conducted a meta-analysis to quantify the risk of progression to type 2 diabetes for women with GDM.MethodsWe systematically searched the major electronic databases with no language restrictions. Two reviewers independently extracted 2 × 2 tables for dichotomous data and the means plus SEs for continuous data. Risk ratios were calculated and pooled using a random effects model.ResultsThere were 39 relevant studies (including 95,750 women) BMI (RR 1.95 [95% CI 1.60, 2.31]), family history of diabetes (RR 1.70 [95% CI 1.47, 1.97]), non-white ethnicity (RR 1.49 [95% CI 1.14, 1.94]) and advanced maternal age (RR 1.20 [95% CI 1.09, 1.34]) were associated with future risk of type 2 diabetes. There was an increase in risk with early diagnosis of GDM (RR 2.13 [95% CI 1.52, 3.56]), raised fasting glucose (RR 3.57 [95% CI 2.98, 4.04]), increased HbA1c (RR 2.56 [95% CI 2.00, 3.17]) and use of insulin (RR 3.66 [95% CI 2.78, 4.82]). Multiparity (RR 1.23 [95% CI 1.01, 1.50]), hypertensive disorders in pregnancy (RR 1.38 [95% CI 1.32, 1.45]) and preterm delivery (RR 1.81 [95% CI 1.35, 2.43]) were associated with future diabetes. Gestational weight gain, macrosomia in the offspring or breastfeeding did not increase the risk.Conclusions/interpretationPersonalised risk of progression to type 2 diabetes should be communicated to mothers with GDM.Systematic review registration:www.crd.york.ac.uk/PROSPERO CRD42014013597Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3927-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Exposure of a developing foetus to maternal gestational diabetes (GDM) has been shown to programme future risk of diabetes and obesity. Epigenetic variation in foetal tissue may have a mechanistic role in metabolic disease programming through interaction of the pregnancy environment with gene function. We aimed to identify genome-wide DNA methylation variation in cord blood and placenta from offspring born to mothers with and without GDM. Pregnant women of South Asian origin were studied and foetal tissues sampled at term delivery. The Illumina HumanMethylation450 BeadChip was used to assay genome-wide DNA methylation in placenta and cord blood from 27 GDM exposed and 21 unexposed offspring. We identified 1485 cord blood and 1708 placenta methylation variable positions (MVPs) achieving genome-wide significance (adjusted P-value <0.05) with methylation differences of >5%. MVPs were disproportionately located within first exons. A bioinformatic co-methylation algorithm was used to detect consistent directionality of methylation in 1000 bp window around each MVP was observed at 74% of placenta and 59% of cord blood MVPs. KEGG pathway analysis showed enrichment of pathways involved in endocytosis, MAPK signalling and extracellular triggers to intracellular metabolic processes. Replication studies should integrate genomics and transcriptomics with longitudinal sampling to elucidate stability, determine causality for translation into biomarker and prevention studies.

Background It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol (LDL-C) on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. Methods and results We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio 0.83, 95%CI 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR 0.79, 95%CI 0.72–0.82). This association was also observed among patients achieving on-statin LDL-C levels < 50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR 0.98, 95%CI 0.94–1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR 0.93, 95%CI 0.90–0.97). Conclusions Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low LDL-C. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.