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.

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 213 and 220% 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.

ObjectivesThis study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.BackgroundHigher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.MethodsWe conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.ResultsPLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.ConclusionsReducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

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.

Common genetic variation in APOA1 associated with increased apoA-I and HDL cholesterol levels did not associate with decreased risk of IHD or MI.

.  Haase CL, Frikke‐Schmidt R, Nordestgaard BG, Kateifides AK, Kardassis D, Nielsen LB, Andersen CB, Køber L, Johnsen AH, Grande P, Zannis VI, Tybjærg‐Hansen A (Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Denmark; University of Crete Medical School, Heraklion, Greece; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA). Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels. J Intern Med 2011; 270: 136–146. Objectives.  To determine whether mutations in APOA1 affect levels of high‐density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population. Background.  Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A‐I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death. Design.  We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case–control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA‐I in human heterozygotes and functional effects of mutations in adenovirus‐transfected mice. Results.  We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6–6.5], 5.5 (95% CI: 2.6–11.7) and 2.5 (95% CI: 1.3–4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case–control study. Furthermore, the ratio of mutant S164 to WT A164 apoA‐I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA‐I, and this finding was confirmed in adenovirus‐transfected mice. Conclusions.  A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.

A large initial HbA reduction and achievement of low HbA levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.

Aims/hypothesis The aims of this work were to assess glycaemic control in metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs. Methods We carried out a population-based cohort study using healthcare databases in northern Denmark during 2000-2012. We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years. Attainment of recommended HbA 1c goals within 6 months of add-on was investigated, using Poisson regression analysis adjusted for age, sex, baseline HbA 1c , diabetes duration, complications and Charlson Comorbidity Index. Results Median metformin treatment duration at intensification was 12 months (interquartile range [IQR] 4-23 months) and pre-intensification HbA 1c was 8.0% (IQR 7.2-9.2%) (64 mmol/mol). Median HbA 1c dropped 1.2% (13 mmol/mol) with a sulfonylurea (SU) add-on, 0.8% (9 mmol/mol) with a dipeptidyl peptidase-4 (DPP-4) inhibitor, 1.3% (14 mmol/mol) with a glucagon-like peptide-1 (GLP-1) receptor agonist, 0.9% (10 mmol/mol) with other non-insulin drugs and 2.4% (26 mmol/mol) with insulin. Compared with SU add-on, attainment of HbA 1c <7% (<53 mmol/mol) was higher with GLP-1 receptor agonists (adjusted RR [aRR] 1.10; 95% CI 1.01, 1.19) and lower with DPP-4 inhibitors (aRR 0.94; 95% CI 0.89, 0.99), other drugs (aRR 0.86; 95% CI 0.77, 0.96) and insulin (aRR 0.88; 95% CI 0.77, 0.99). The proportion of metformin add-on users who attained HbA 1c <7% (<53 mmol/mol) increased from 46% in 2000-2003 to 59% in 2010-2012, whereas attainment of HbA 1c <6.5% (<48 mmol/mol) remained 30% among patients aged <65 years without comorbidities. Conclusions/interpretation Among early type 2 diabetes patients receiving their first metformin add-on treatment, HbA 1c reduction with different non-insulin drugs is similar to, and comparable with, that observed in randomised trials, yet 41% do not achieve HbA 1c <7% (<53 mmol/mol) within 6 months.