Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM-INSULIN trial.

AIMS: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. METHODS: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. RESULTS: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. CONCLUSION: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

Impact of diabetes duration on hypoglycaemia in patients with type 2 diabetes treated with insulin glargine or NPH insulin.

AIM: To compare the impact of diabetes duration on hypoglycaemia in patients with type 2 diabetes mellitus (T2DM) treated with insulin glargine or NPH insulin. METHODS: A pooled analysis of 24-week patient level data from randomized controlled studies comparing once-daily insulin glargine with once-daily NPH insulin in insulin-naïve adult patients with T2DM was performed, stratifying patients into quartiles by duration of diabetes: <5.8 years; 5.8 to <9.2 years; 9.2 to <14 years and ≥14 years. Daytime and nocturnal hypoglycaemia events were evaluated. RESULTS: Data from 2330 patients in four randomized controlled trials were included in the analysis; 1258 treated with insulin glargine and 1072 with NPH insulin. The rates of daytime hypoglycaemia were similar for insulin glargine and NPH insulin, irrespective of disease duration. Patients with longer T2DM duration treated with glargine experienced greater glycated haemoglobin A1c (HbA1c) reductions. Rates of severe nocturnal hypoglycaemia and nocturnal hypoglycaemia [self-monitored blood glucose < 70 mg/dl (3.89 mmol/l) and < 50 mg/dl (2.78 mmol/l)] were all significantly and positively correlated with the duration of diabetes for patients treated with NPH insulin but not with insulin glargine. Despite improvements in HbA1c, rates of symptomatic nocturnal hypoglycaemia were significantly lower with insulin glargine than with NPH insulin in patients with longer T2DM duration. CONCLUSION: There is a lower risk for nocturnal hypoglycaemia with insulin glargine than with NPH insulin. When considering diabetes duration, insulin glargine (compared to NPH insulin) may be particularly beneficial in patients with a longer duration of T2DM.

Association of sulfhydryl oxidase and xanthine oxidase in bovine mammary tissue.

The presence of antigenically active xanthine oxidase was indicated in various relatively purified preparations of sulfhydryl oxidase obtained from bovine milk. Evidence for formation of a complex of the two enzymes was obtained by double immunodiffusion. Furthermore, sodium dodecylsulfate-gel electrophoresis of sulfhydryl oxidase and xanthine oxidase model mixtures indicated that high molecular weight species were present that reacted with both antisulfhydryl oxidase and antixanthine oxidase. Similar gel electrophoretic patterns visualized by protein-dye binding methods revealed a distinct band (greater than 200 kdalton) was formed upon incubation of mixtures of the two enzymes, the presence of which was unaffected by reduction of protein disulfide bonds. Immunofluorescent staining techniques showed both enzymes in the apical plasma membrane. Because sulfhydryl oxidase previously has been shown to catalyze conversion of the dehydrogenase form of xanthine oxidase to the oxidase form, this conversion may occur when xanthine oxidase contacts sulfhydryl oxidase in the apical plasma membrane. This conversion and the resulting potential for production of active oxygen species could be significant to membranotropic processes, such as fat globule secretion, and to the oxidative stability of the milk fat globule membrane.

Effect of histamine on bovine milk fatty acids.

Milk histamine content was monitored over the estrous cycle of several cows. Concentrations of histamine in the milk were maximal between days 0 and 1 and between days 4 and 7 of the estrous cycle. One quarter of a mammary gland of each of six cows was infused with 10 mg histamine free base. Milk samples were taken at 0, 4 and 10 hr, then analyzed for fatty acid composition. The 4-hr samples showed an increase in the proportion of short and medium length fatty acids, an increase in myristoleic, palmitoleic, oleic and linoleic acids and a decrease in stearic acid. The 10-hr samples showed a decrease in proportion of short and medium length fatty acids, a decrease in palmitic acid and an increase in stearic acid, while oleic acid and linoleic acid continued to increase from preinfusion. Linolenic acid showed no significant change during the experiment. Milk from one normal and one mastitic quarter of the mammary glands of several cows showed a significantly higher histamine content in mastitic milk than in normal milk.

Transport of bovine milk xanthine oxidase into mammary glands of the rat.

This research investigated transport of bovine milk xanthine oxidase into mammary glands of the lactating rat. Transport capability suggested an exogenous, nonmammary, source for the enzyme. Five lactating rats were injected intracardially with 100 microgram of purified iodine-125 labeled xanthine oxidase and five were injected with 100 microgram of the enzyme unpurified. Four hours later the rodents were hand-milked, and radiation was confirmed in all samples by liquid scintillation counting. Counts were recorded per volume of milk and the percentage radiation was computed. Autoradiographs of the rats indicated radiation almost exclusively associated with the mammary glands. Greatest concentration of radioactivity was in the micellar casein fraction of milk, and a compound of high molecular weight, presumably [iodine-125]xanthine oxidase, was confirmed by gel filtration of the casein. Results suggest that the compound was transported into the mammary glands. The degree of transport was dependent upon the stage of lactation.