Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

. tumour necrosis factoralpha plasma level in patients with type 1 diabetes mellitus and its association with glycaemic control and cardiovascular risk factors. J Intern Med 2000: 248: 67±76.Objectives. Diabetic patients reveal a significant increase in their cardiovascular risk. Beside glycaemic control and management of established risk factors, determination of cytokines, like serum levels of tumour necrosis factor-alpha (TNF-a), might offer a tool to determine patients at high risk. The cytokine TNF-a reveals a complex relationship with diabetes. It is involved in beta-cell damage leading to type 1 diabetes, causes insulin resistance associated with obesity and is of influence in the formation of atherosclerotic vascular lesions. We were interested in the possible association of this cytokine with metabolic control and cardiovascular risk factors in patients with type 1 diabetes. Design and Subjects. TNF-a plasma levels were determined in 44 outdoor patients (15 women, 29 men) with type 1 diabetes mellitus (mean duration 11.2 6 8.7 years) and in 24 healthy controls by use of a solid phase enzyme amplified sensitivity immunoassay (TNF-a ELISA, Biosource Fleurus, Belgium). None of our study participants suffered from inflammatory or other concurrent diseases. Relationships between variables were evaluated by non-parametric Spearman correlation coefficients.Results. TNF-a plasma levels were significantly higher in diabetic patients (19.3 6 7.5 pg mL 21 ) than in non-diabetic subjects (11.1 6 5.8 pg mL 21 ; P , 0.023), and revealed a significant positive correlation with glycated haemoglobin (HbA 1c ) (r = 0.43; P , 0.004) and fructosamine (r = 0.31; P , 0.049) values, and a negative correlation with HDL cholesterol (r = ±0.36; P , 0.018) and apoAIlevels (r = ±0.37; P , 0.015). These relationships could be observed in patients with a duration of diabetes for more than 5 years, as well as in patients with a shorter duration of diabetes. In the male group, TNF-a plasma levels revealed a significant positive correlation with plasma levels of thiobarbituric acid reacting substances (r = 0.61; P , 0.001). Plasma levels of thiobarbituric acid reacting substances showed a positive correlation with the duration of diabetes (r = 0.58; P , 0.008), as well as with the serum levels of the vascular adhesion molecules intercellular adhesion molecule (ICAM) (r = 0.34; P , 0.051) and vascular cell adhesion molecule (VCAM) (r = 0.30; P , 0.052). Conclusions. Our data indicate that TNF-a plasma levels are increased in type 1 diabetes mellitus and reveal a significant association with metabolic longterm control parameters, HbA 1c and fructosamine for glycaemic control, and HDL cholesterol for triglyceride metabolism, as well with lipid peroxidation.

Accumulating evidence suggests that the immune system is involved in atherogenesis, such as the correlation of the antibody titre to heat shock protein (hsp) with atherosclerotic lesions in the carotid and coronary arteries. Because the prognostic value of the hsp antibody titre for future cardiovascular events has not been evaluated until now, we performed a follow-up study on 195 subjects without a history of established cardiovascular risk factors (e.g. hypercholesterolaemia, diabetes, smoking), recruited for hsp antibody titre determination in 1995. Cardiovascular events were defined as unstable angina with the need for hospitalisation, myocardial infarction, re-vascularisation (PTCA, bypass), stroke and cardiovascular death. Among 79 men with coronary artery disease defined by coronary angiography, hsp antibody titres were signficantly higher in those with future cardiovascular events (467.0 ± 56.3) than in patients without further events (351.0 ± 23.3; p < 0.049). Because anti-hsp-antibody titres might be of prognostic value for coronary artery disease, patients with an increased hsp antibody titre should obtain intensive management of classical risk factors.

To our knowledge, our population of elderly patients treated with adjuvant trastuzumab is the largest analyzed so far. The beneficial long-term results were comparable to those in the younger cohorts. Although the risk of cardiotoxicity increased significantly with age, it also remained manageable in older patients. Thus, chronological age alone should not preclude HER2 antibody treatment.

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