Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor 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. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

MMDT Short Term Bond Fund : 2015 Investment Circular

OBJECTIVE:Despite the common use of non-fasting measurements for lipid profile in children it remains unclear as to the extent non-fasting conditions have on laboratory results of lipids measurements. We aimed to assess the impact of non-fasting lipid profile on the occurrence of dyslipidemia in children. MATERIALS AND METHODS:Basic lipid profile including: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), as well as small, dense-LDL-C (sd-LDL-C), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB) and lipoprotein(a) [Lp(a)], were measured in 289 presumably healthy children aged 9-11 in both fasting and non-fasting condition. The clinical impact of non-fasting lipid profile was evaluated individually for each child with estimation of false positive (FP) and false negative (FN) results. RESULTS:The highest percentage of FP results in non-fasting condition was observed for TG (42.3%) being significantly higher when compared to FN results (p = 0.003). In contrast, the highest percentage of FN results in a non-fasting state were shown for LDL-C (14.3%), but the difference was statistically insignificant when compared to FP results. When comparing fasting and non-fasting lipid profile a number of significant differences was shown for: TG (p<0.001), HDL-C (p = 0.002) LDL-C (p<0.001) and ApoAI (p<0.001), respectively. The occurrence of dyslipidemia, recognized on the basis of non-fasting lipids was significantly higher (p = 0.010) when compared to fasting lipid profile. CONCLUSIONS:A higher occurrence of dyslipidemia, based on the measurement of non-fasting lipids in children, is suggestive of possible disorders in lipid metabolism. However, accurate identification of dyslipidemia by assessment of non-fasting lipids requires the establishment of appropriate cut-off values for children

Association between Fasting Glucose Concentration, Lipid Profile and 25(OH)D Status in Children Aged 9–11

Background: The aim of this study was to assess the relationship between vitamin D status and the prevalence of dyslipidemia and impaired fasting glucose (IFG) in children. Methods and Summary: 284 children (150 boys and 134 girls) aged 9&ndash;11 were included in the study. Children with deficient 25(OH)D (25-hydroxycholecalciferol) levels &le;20 ng/mL (50 nmol/L) were characterized by a more frequent occurrence of impaired fasting glucose (IFG) (Odd ratios (OR) = 1.966, 95% confidence interval (CI): 1.055&ndash;3.663; p = 0.033) when compared to children with 25(OH)D &gt;20 ng/mL. Serum 25(OH)D with concentration lower by 1 ng/mL (2.5 nmol/L) was linked to higher fasting glucose (by 0.25 mg/dL, 0.013 mmol/L; p = 0.017), higher total cholesterol (TC) by almost 1 mg/dL (0.96 mg/dL, 0.25 mmol/L; p = 0.006) and higher high-density lipoprotein cholesterol (HDL-C) (by 0.57 mg/dL, 0.015 mmol/L; p &lt; 0.001). Conclusion: 25(OH)D deficiency may negatively affect fasting glucose and total cholesterol concentration in children aged 9&ndash;11. Vitamin D-deficient children are twice as likely to develop prediabetes as reflected by impaired fasting glucose when compared to those with a 25(OH)D level above 20 ng/mL (50 nmol/L)

The impact of non-fasting measurements on clinical significance.

<p><b>NC</b> (No Change)- measurements in fasting and non-fasting state showed the same lipid classification; <b>FP</b> (False Positive);<b>FN</b> (False Negative);<b>∑</b> (the sum of <b>FP</b> and <b>FN</b> results); <b>TC</b>-total cholesterol; <b>TG</b>-triglycerides; <b>LDL-C</b>-low density lipoprotein cholesterol; <b>HDL-C</b>-high density lipoprotein cholesterol; <b>sd-LDL-C</b>-small, dense low density lipoprotein cholesterol; <b>ApoB</b>- apolipoprotein B; <b>ApoAI</b>-apolipoprotein AI; <b>Lp(a)</b>- lipoprotein (a); <b>non-HDL-C</b>- non high density lipoprotein cholesterol [TC-(HDL-C)]; <b>TG/HDL-C</b>–triglycerides to high density lipoprotein cholesterol ratio.</p

The percentage of abnormal lipid parameters results in fasting vs. non-fasting state [N = 289].

<p>*Cut-off point for lipids in accordance with The National Heart, Lung and Blood Institute (NHLBI) guideline [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198433#pone.0198433.ref002" target="_blank">2</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0198433#pone.0198433.ref006" target="_blank">6</a>]. <b>TC</b>-total cholesterol; <b>TG</b>-triglycerides; <b>LDL-C</b>-low density lipoprotein cholesterol; <b>HDL-C</b>-high density lipoprotein cholesterol; <b>sd-LDL</b>-small, dense low density lipoprotein cholesterol; <b>Apo B</b>- apolipoprotein B; <b>ApoAI</b>-apolipoprotein A1; <b>Lp(a)</b>- lipoprotein (a).</p

The occurrence of dyslipidemia according to BMI category.

<p><b>BMI</b>: body mass index.</p

Comparison of lipid parameters in fasting vs. non-fasting state (based on BMI percentiles).

<p>Comparison of lipid parameters in fasting vs. non-fasting state (based on BMI percentiles).</p

The percentage of diagnosis of dyslipidemias with the use of two lipid indices: Non-HDL-C and TG/HDL-C in fasting/non-fasting state.

<p>non-HDL-C- non high density lipoprotein cholesterol [TC-(HDL-C)]; <b>TG/HDL-C</b>–triglycerides to high density lipoprotein cholesterol ratio.</p

Occurrence of abnormal lipid parameters: Comparison on the basis of BMI and fasting/non-fasting status.

<p>Occurrence of abnormal lipid parameters: Comparison on the basis of BMI and fasting/non-fasting status.</p

Baseline characteristics of study participants.

<p>Baseline characteristics of study participants.</p