Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study.

AIMS: To evaluate the comparative cardiovascular disease (CVD) safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in head-to-head comparisons with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulphonylureas or insulin, when added to metformin, as used in 'real-world' patients with type 2 diabetes mellitus (T2DM). METHODS: Within a large US commercial health plan database linked to laboratory test results, we identified three pairwise 1 : 1 propensity-score-matched cohorts of patients with T2DM aged ≥18 years treated with metformin who initiated a GLP-1 RA or a comparator, i.e. DPP-4 inhibitor (n = 35 534), second-generation sulphonylureas (n = 28 138) or insulin (n = 47 068), between 2005 and 2013. We examined the association between drug initiation and a composite CVD endpoint, comprising hospitalizations for acute myocardial infarction, unstable angina, stroke or coronary revascularization. RESULTS: During the course of 1 year, there were 13.9 and 13.7 CVD events per 1000 person-years among propensity-score-matched initiators of GLP-1 RAs versus DPP-4 inhibitors [hazard ratio (HR) 1.02; 95% confidence interval (CI) 0.84-1.24]; and 12.1 versus 14.0 events among initiators of GLP-1 RAs versus sulphonylureas (HR 0.86; 95% CI 0.69-1.08). The effect estimates for GLP-1 RAs versus insulin were sensitive to the adjustment for glycated haemoglobin, after which the HR was 1.01 (95% CI 0.73-1.41). Results were robust across several sensitivity analyses, including an as-treated analysis considering up to 8.7 years of follow-up. CONCLUSIONS: This large study, performing head-to-head comparisons of GLP-1 RAs with other antidiabetic agents in real-world patients, provides estimates of relative safety precise enough to exclude large differences in CVD risk and adds further understanding to results from recent clinical trials.

Lipid biomarkers, hormone therapy and the risk of venous thromboembolism in women.

BACKGROUND: Published reports of a relationship between lipids and incident venous thromboembolism (VTE) are conflicting. OBJECTIVES: To clarify the relationship between lipids and VTE risk in healthy women, including potential effect modification by hormone therapy (HT). PATIENTS/METHODS: Among 27 081 initially healthy women followed prospectively for incident VTE, we measured a full panel of lipid biomarkers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides and apolipoproteins A-I (apo A-I) and B(100). RESULTS: During a median follow-up of 11.4 years, VTE occurred in 355 women. We observed no relationship between any of the lipids and VTE risk. However, when unprovoked VTE was considered separately (n=161), both HDL-C and apo A-I were positively associated with risk. Fully adjusted hazard ratios (HR) and 95% confidence intervals (CI) for extreme tertiles of HDL-C and apo A-I were 1.75 (1.13-2.73) and 1.70 (1.10-2.62), respectively. After stratifying by HT use, this relationship was present only among HT users; the HRs for unprovoked VTE for extreme tertiles of HDL-C and apo A-I were 3.58 (1.69-7.58) and 2.88 (1.29-6.42) among users, but only 0.79 (0.39-1.62) and 0.89 (0.50-1.57) among non-users. The interactions were statistically significant (each Pinteraction<0.05). CONCLUSIONS: We observed little evidence that lipid levels predict risk of incident VTE among non-users of HT. High levels of HDL-C and apo A-I associate with unprovoked VTE risk among HT users. This observation likely reflects prothrombotic effects of HT that are concomitant with HDL-C and apo A-I levels, rather than direct effects of those lipids.

Effect of valsartan compared with valsartan/hydrochlorothiazide on plasma levels of cellular adhesion molecules: the Val-MARC trial.

BACKGROUND: The Val-MARC trial showed that the angiotensin receptor blocker valsartan reduces high-sensitivity C reactive protein (hsCRP) levels, an effect that is independent of blood pressure, and seems to be neutralised by the addition of hydrochlorothiazide. OBJECTIVE: To evaluate whether valsartan influences soluble intercellular adhesion molecule 1 (sICAM-1) or vascular cell adhesion molecule 1 (sVCAM-1). DESIGN: Post-hoc analysis from a randomised trial. SETTING: Val-MARC trial. PATIENTS: 1188 patients with stage 2 hypertension. INTERVENTION: Random allocation to either valsartan 320 mg (n = 607) or combination therapy with valsartan/hydrochlorothiazide 320 mg/12.5 mg (n = 581) for 6 weeks. MAIN OUTCOME MEASURE: Change in sICAM-1 and sVCAM-1 from baseline to 6 weeks of follow-up RESULTS: After treatment, median (interquartile range) sICAM-1 levels were reduced by both valsartan alone (-4 (-25 to 16) ng/ml, p = 0.005) and valsartan/hydrochlorothiazide (-4 (-22 to 17) ng/ml, p = 0.028), such that the between-group difference was not significant (p = 0.7). The median percentage change from baseline was small in both groups (-1.6% and -1.3%). Median (interquartile range) sVCAM-1 levels were reduced by both valsartan alone (-13 (-70 to 42) ng/ml, p = 0.001) and valsartan/hydrochlorothiazide (-26 (-88 to 38), p<0.001); the between-group difference was of borderline significance (p = 0.051). The median percentage change from baseline was small (-2.1% and -4.4%). The reduction of sICAM-1 and sVCAM-1 was independent of blood pressure reduction (rs = 0.03 and rs = 0.06 for the relationship of change in systolic blood pressure with change in sICAM-1 and sVCAM-1, respectively). CONCLUSION: In contrast to hsCRP, both valsartan and valsartan/hydrochlorothiazide induced reductions of sICAM-1 and sVCAM-1 in the Val-MARC trial. These effects, although statistically significant, were small and independent of changes in blood pressure.

Lipid levels and the risk of ischemic stroke in women.

OBJECTIVE: To evaluate the association between total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C ratio, and non-HDL-C with the risk of ischemic stroke in a large cohort of apparently healthy women. METHODS: Prospective cohort study among 27,937 US women aged > or =45 years participating in the Women's Health Study who provided baseline blood samples. Stroke occurrence was self-reported and confirmed by medical record review. We categorized plasma lipid measurements into quintiles. We used Cox proportional hazards models to evaluate the association between lipids and risk of ischemic stroke. RESULTS: During 11 years of follow-up, 282 ischemic strokes occurred. All lipid levels were strongly associated with increased risk of ischemic stroke in age-adjusted models. The association attenuated particularly for HDL-C after adjustment for potential confounders. For the comparison of the highest to the lowest quintile, the multivariable-adjusted hazard ratios (95% CI; p for trend across mean quintile values) of ischemic stroke were 2.27 (1.43, 3.60; p(trend) < 0.001) for total cholesterol; 1.74 (1.14, 2.66; p(trend) = 0.003) for LDL-C; 0.78 (0.52, 1.17; p(trend) = 0.27) for HDL-C; 1.65 (1.06, 2.58; p(trend) = 0.02) for the total cholesterol to HDL-C ratio; and 2.45 (1.54, 3.91; p(trend) < 0.001) for non-HDL-C. CONCLUSIONS: In this large cohort of apparently healthy women, total cholesterol, low-density lipoprotein cholesterol, the total cholesterol to high-density lipoprotein cholesterol ratio, and non-high-density lipoprotein cholesterol were significantly associated with increased risk of ischemic stroke.