The 'brick diet' and postprandial insulin: a practical method to balance carbohydrates ingested and prandial insulin to prevent hypoglycaemia in hospitalized persons with diabetes.

AIM: Insulin is the preferred treatment for the control of diabetes in hospital, but it raises the risk of hypoglycaemia, often because oral intake of carbohydrates in hospitalized persons is lower than planned. Our aim was to assess the effect on the incidence of hypoglycaemia of giving prandial insulin immediately after a meal depending on the amount of carbohydrate ingested. METHODS: A prospective pre-post intervention study in hospitalized persons with diabetes eating meals with stable doses of carbohydrates present in a few fixed foods. Foods were easily identifiable on the tray and contained fixed doses of carbohydrates that were easily quantifiable by nurses as multiples of 10 g (a 'brick'). Prandial insulin was given immediately after meals in proportion to the amount of carbohydrates eaten. RESULTS: In 83 of the first 100 people treated with the 'brick diet', the oral carbohydrate intake was lower than planned on at least one occasion (median: 3 times; Q1-Q3: 2-6 times) over a median of 5 days. Compared with the last 100 people treated with standard procedures, postprandial insulin given on the basis of ingested carbohydrate significantly reduced the incidence of hypoglycaemic events per day, from 0.11 ± 0.03 to 0.04 ± 0.02 (P < 0.001) with an adjusted incidence rate ratio of 0.70 (95% confidence interval 0.54-0.92; P = 0.011). CONCLUSIONS: In hospitalized persons with diabetes treated with subcutaneous insulin, the 'brick diet' offers a practical method to count the amount of carbohydrates ingested, which is often less than planned. Prandial insulin given immediately after a meal, in doses balanced with actual carbohydrate intake reduces the risk of hypoglycaemia.

Cardiovascular complications and drug prescriptions in subjects with and without diabetes in a Northern region of Italy, in 2002 and 2012.

BACKGROUND AND AIMS: In contrast to the well-documented global prevalence of diabetes, much less is known about the epidemiology of cardiovascular (CV) complications in recent years. We describe the incidence of major CV events, deaths and drug prescribing patterns from 2002 to 2012 in subjects with (DM) or without diabetes mellitus (No DM). METHODS AND RESULTS: Subjects and outcomes were identified using linkable health administrative databases of Lombardy, a region in Northern Italy. A logistic regression model was used to compare myocardial infarction (MI), stroke, major amputation and death between DM and No DM in 2002 and 2012 and between the two index years in each population. The interaction between years and diabetes was introduced in the model. From 2002 to 2012 the incidence of major CV complications and death fell in both groups with a larger reduction among DM only for CV events: OR (95% CI) for the interaction 0.86 (0.79-0.93) for MI, 0.89 (0.82-0.96) for stroke, 0.78 (0.57-1.06) for major amputations. CV prevention drugs rose considerably from 2002 to 2012 particularly in DM and a switch towards safer antihyperglycemic drugs was also observed. CONCLUSIONS: Major CV complications and death declined from 2002 to 2012 in both DM and No DM. This might be due to a larger increase in prescriptions of CV drugs in DM and a relevant change toward recommended antihyperglycemic drugs.

A multicenter observational study on the management of hyperglycemia in patients with acute coronary syndrome.

AIM: To assess the prevalence, risk and management of hyperglycemia in patients with acute coronary syndrome (ACS). DESIGN: a multicenter prospective observational study of a representative sample of patients with ACS consecutively admitted to intensive cardiac care units (ICCU). SETTING: 31 out of 61 ICCUs in Lombardy, the most heavily populated Italian region. From May 2009 to April 2010 1260 patients (69.4% male; mean age 68 ± 13 years) were included in the study: 301 (23.9%) were known diabetic patients (D) and 265 (21.0%) had hyperglycemia (H) (blood glucose >180 mg/dL) at hospital admission, 174 with a history of diabetes (D+H+) and 91 without (D-H+). On the first day after admission intravenous insulin infusion was prescribed to 72 D+H+ (41.4%) and 10 D-H+ (11.0%), according to different protocols. Approximately one third of D+H+ patients (59) and one fifth (17) of D-H+ maintained mean blood glucose higher than 180 mg/dL during the first day in the ICCU. Patients with diabetes or hyperglycemia had a higher incidence of major adverse cardiovascular events or death in hospital. However, at multivariable analysis neither diabetes nor blood glucose at admission was associated with a poor prognosis whereas mean blood glucose on the first day was an independent negative prognostic predictor (OR 1.010, 95% CI 1.002-1.018, p = 0.016). CONCLUSION: Hyperglycemia is frequent in patients with ACS and is independently associated with a poor in-hospital prognosis if it persists in first day. Unfortunately, however, this condition is still poorly treated, with far from optimal blood glucose control.

Elevated risk of death and major cardiovascular events in subjects with newly diagnosed diabetes: findings from an administrative database.

AIMS: To investigate the incidence of major cardiovascular complications and mortality in the first years of follow-up in patients with newly diagnosed diabetes. METHODS AND RESULTS: We examined incidence rates of hospitalization for cardiovascular reasons and death among new patients with diabetes using the administrative health database of the nine million inhabitants of Lombardy followed from 2002 to 2007. Age and sex-adjusted rates were calculated and hazard ratios (HR) were estimated with a matched population without diabetes of the same sex, age (± 1 year) and general practitioner. There were 158,426 patients with newly diagnosed diabetes and 314,115 subjects without diabetes. Mean follow-up was 33.0 months (SD ± 17.5). 9.7% of patients with diabetes were hospitalized for cardiovascular events vs. 5.4% of subjects without diabetes; mortality rate was higher in patients with diabetes (7.7% vs. 4.4%). The estimated probability of hospitalization during the follow up was higher in patients with diabetes than in subjects without for coronary heart disease (HR 1.4, 95% CI 1.3-1.4), cerebrovascular disease (HR 1.3.95% CI 1.2-1.3), heart failure (HR 1.4, 95% CI 1.3-1.4) as was mortality (HR 1.4, 95% CI 1.4-1.4). Younger patients with diabetes had a risk of death or hospital admission for cardio-cerebrovascular events similar to subjects without diabetes ten years older. CONCLUSIONS: The elevated morbidity and mortality risks were clear since the onset of diabetes and rose over time. These data highlight the importance of prompt and comprehensive patients care in addition to anti-diabetic therapy in patients with newly diagnosed diabetes.

Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study.

AIMS: To describe trends in diagnosed diabetes prevalence, incidence and mortality from 2000 to 2007 in the most heavily populated Italian region. METHODS: We examined the prevalence and incidence rates of Type 1 and Type 2 diabetes and yearly mortality rates among individuals with diabetes from 2000 to 2007 using an administrative health database of prescription, disease-specific exemption and hospitalization records of more than 9 million inhabitants of Lombardy. Age- and sex-specific rates were calculated and temporal trends for subjects aged ≥ 30 years were analysed. RESULTS: The crude point diabetes prevalence rose from 3.0% in 2000 to 4.2% in 2007, a 40% increase. The incidence remained stable during the study period with a rate of 4/1000 per year. Overall mortality declined from 43.2/1000 in 2001 to 40.3/1000 in 2007 (6.7% decrease) at a rate slightly higher than that of the general population (4.8% decrease). Our projection in subjects aged ≥ 30 years indicates that the prevalence will rise continuously over the next years, reaching 11.1% in 2030. CONCLUSIONS: The prevalence of diabetes increased substantially between 2000 and 2007, mainly because there are more patients with a new diagnosis each year than those who die. The increase observed by 2007 almost reached the World Health Organization prediction for 2030. Our analyses suggest that the increase will continue over the next few decades. These data are important for defining the burden of diabetes in the near future, to help in planning health services and ensure proper allocation of resources.

Early coronary reperfusion blunts the procoagulant response of plasminogen activator inhibitor-1 and von Willebrand factor in acute myocardial infarction.

The effects of early coronary recanalization on the plasma levels of two procoagulant acute phase proteins, the fastacting plasminogen activator inhibitor and von Willebrand factor, were investigated in 24 patients with myocardial infarction receiving intravenous recombinant tissue-type plasminogen activator (rt-PA) within 6 h of the onset of symptoms. Coronary angiography was performed before and 90 min after the start of rt-PA infusion. Continuous electrocardiographic recordings and 4 h plasma creatine kinase MB isoenzyme (CK MB) were performed over the first 24 h. Plasma plasminogen activator inhibitor activity, von Willebrand factor and C-reactive protein were measured before rt-PA infusion, daily for the first 3 days and after 90 days. In the entire group, plasminogen activator inhibitor activity peaked at 24 h (day 1), representing a significant increase over values at all other times (p = 0.03). von Willebrand factor was higher in the first 2 days of infarction compared with after 90 days (p = 0.001). C-reactive protein peaked on day 2, with an eightfold increase over values on admission (p = 0.001). In the 16 patients with a patent infarct-related artery at 90 min, infarct size estimated by integrated 24 h CK MB, time for ST segment elevation to decrease to half-maximum and peak C-reactive protein were reduced significantly by more than twofold compared with values in the 8 patients with an occluded artery at 90 min. The patients with early recanalization also had lower plasminogen activator inhibitor activity on day 2 (p = 0.05) and day 3 (p = 0.02) and lower 0 to 72 h averaged von Willebrand factor (p = 0.01). Thus, early coronary recanalization curtails the response of plasminogen activator inhibitor activity and von Willebrand factor to myocardial infarction, most likely by reducing the extent of ischemia and necrosis and the consequent acute phase reaction. By blunting the early postinfarction procoagulant state, prompt recanalization may reduce the risk of thromboembolic complications in the first days after myocardial infarction.

Heparin counteracts the antiaggregating effect of prostacyclin by potentiating platelet aggregation.

It has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1 and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.

Von Willebrand factor, plasminogen activator inhibitor-1 and C-reactive protein are markers of thrombolytic efficacy in acute myocardial infarction.

Plasma von Willebrand factor, plasminogen activator inhibitor activity and C-reactive protein were assessed as markers of coronary recanalisation in 30 patients with acute myocardial infarction receiving tissue-type plasminogen activator (t-PA). Blood samples were taken before t-PA (time 0), 4-hourly for 24 h and daily up to 72 h. A continuous electrocardiogram was recorded in the first 24 h. Coronary arteriography was performed 90 min and 24 h after the start of t-PA. Patients with a patent infarct artery (n = 17), compared to those with occluded artery (n = 13), showed a fall in von Willebrand factor from 0 to 24 h (p = 0.001), a greater fall in plasminogen activator inhibitor from 24 to 48 h (p = 0.04) and a fall in C-reactive protein from 48 to 72 h (p = 0.002). The accuracy of these indices compared favourably with time to peak plasma MB creatine kinase and > or = 50% resolution of maximal ST-deviation on the electrocardiogram. Thus, changes in plasma von Willebrand factor, plasminogen activator inhibitor and C-reactive protein during the first 3 days of myocardial infarction are indicative of thrombolytic efficacy. Their concordant behaviour may reflect a common regulatory mechanism.

Plasma and platelet lipid composition and platelet aggregation by arachidonic acid in women on the pill.

Sensitivity to induction of platelet aggregation by arachidonic acid (AA) and changes in plasma and platelet polyunsaturated fatty acid distribution were studied in seven women before and after six months of oral contraceptive (OC) treatment with a combination of d-norgestrel (0.25 mg) and ethinylestradiol (0.05 mg). Special interest was focused on AA because certain metabolites of fatty acid induce platelets to aggregate and are considered to play a crucial role in thromboembolic processes. In plasma, AA concentrations increased slightly, but significantly, in both the free fatty acid (FFA) and phospholipid fractions; in platelets AA increased in the phospholipid and neutral lipid fractions. The threshold aggregating concentration (TAC) of AA was significantly reduced in platelets of women after six months of OC treatment (0.65 +/- 0.08 versus 0.30 +/- 0.04 mM). This suggests that changes in platelet fatty acid composition may be associated with in vitro changes in platelet sensitivity to AA. Such changes may contribute to the thrombotic tendency associated with OC treatment.

PIP: Sensitivity to induction of platelet aggregation by (AA) arachidonic acid and changes in plasma and platelet polyunsaturated fatty acid distribution were studied in 7 women before and after 6 months of (OC) oral contraceptive treatment with a combination of d-norgestrel (0.25 mg) and ethinyl estradiol (0.05 mg). Special interest was focused on AA because certain metabolites of this fatty acid induce platelets to aggregate and are considered to play a crucial role in thromboembolic processes. In plasma, AA concentrations increased slightly, but significantly, in both the free fatty acid and phospholipid fractions; in platelets AA increased in the phospholipid and neutral lipid fractions. The threshold aggregating concentration of AA was signifcantly reduced in platelets of women after 6 months of OC treatment (0.65 + or - 0.08 versus 0.30 + or -0.04 mM). This suggests that changes in platelet fatty acid composition may be associated with in vitro changes in platelet sensitivity to AA. Such changes may contribute to the thrombotic tendency associated with OC treatment.

Increased susceptibility to the anticoagulant effect of warfarin in mice bearing the Lewis lung carcinoma. Role of vitamin K deficiency.

This study reports an increased susceptibility to warfarin anticoagulation in mice bearing an experimental tumour, the Lewis lung carcinoma. In these animals, following a single i.v. injection of warfarin, the prothrombin complex activity decreased normally but recovered far slower than in controls, while the rate of degradation of the clotting factors was not modified. At the level of the vitamin K-dependent liver carboxylase, it was possible to demonstrate an increase in the endogenous substrate (reflecting an impairment of the carboxylase vitamin K dependent system). This abnormality was reversed by vitamin K administration and can be reasonably ascribed to a vitamin K deficiency in association with tumour growth.

Moderate anticoagulation by salicylate prevents thrombosis without bleeding complications. An experimental study in rats.

It has previously been shown that salicylate (S) acts as a vitamin K (vit K)-antagonist inducing a decrease in plasma levels of vit K-dependent clotting factors and inhibiting the vit K-dependent carboxylation reaction in the liver. In this study we evaluated whether this biochemical effect had a possible functional role. Indeed, we tested in rats the antithrombotic potency of S (175 mg/kg/i.p. twice a day for 3 days) on experimentally induced venous thrombosis. Its possible haemorrhagic effect was evaluated by measuring the bleeding time. Low-dose warfarin (W) (0.2, 0.1, 0.1 mg/kg/i.v. for 3 days) was utilized as control drug. To check for a possible potentiation between S and W, we tested the effects of their combination (S + W). Thrombotest was used to monitor the anticoagulant effect of each treatment. The incidence of thrombus formation, after venous stasis, was not significantly affected by any of the treatments used, but a significant reduction in thrombus weight was observed after either S or W treatment. Both drugs partially prolonged the Thrombotest without affecting either the bleeding time or the peri-operative mortality (mainly due to internal bleeding). When the combination S + W was used, no significant benefit was observed on the prevention of thrombus incidence or weight, although a marked Thrombotest prolongation was recorded. On the other hand this combination resulted in a pronounced bleeding tendency, as expressed in a significant prolongation of bleeding time and increased total mortality. Thus S, at doses inducing moderate anticoagulation may prevent venous thrombosis without relevant bleeding complications.

Effects of low-dose aspirin on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP)--Hypertension study.

Nonsteroidal antiinflammatory drugs may affect blood pressure (BP) control in hypertensive patients receiving drug treatment, but data on the effects of low-dose aspirin are scanty. This study assessed the effects of chronic treatment with low doses of aspirin (100 mg/day) on clinic and ambulatory systolic (SBP) and diastolic (DBP) BP in hypertensives on chronic, stable antihypertensive therapy. The study was conducted in the framework of the Primary Prevention Project (PPP), a randomized, controlled factorial trial on the preventive effect of aspirin or vitamin E in people with one or more cardiovascular risk factors. Fifteen Italian hypertension units studied 142 hypertensive patients (76 men, 66 women; mean age 59 +/- 5.9 years) treated with different antihypertensive drugs: 71 patients were randomized to aspirin and 71 served as controls. All patients underwent a clinic BP evaluation with an automatic sphygmomanometer and a 24-h ambulatory BP monitoring, at baseline and after 3 months of aspirin treatment. At the end of the study the changes in clinic SBP and DBP were not statistically different in treated and untreated subjects. Ambulatory SBP and DBP after 3 months of aspirin treatment were similar to baseline: deltaSBP -0.5 mmHg (95% confidence intervals [CI] from -1.9 to +2.9 mm Hg) and deltaDBP -1.1 mm Hg (95% CI from -2.5 to +0.3 mm Hg). The pattern was similar in the control group. No interaction was found between aspirin and the most used antihypertensive drug classes (angiotensin converting enzyme inhibitors and calcium antagonists). Despite the relatively small sample size our results seem to exclude any significant influence of low-dose aspirin on BP control in hypertensives under treatment.

Effects of vitamin E on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP)--Hypertension study.

A randomized controlled open trial studied the effect of vitamin E supplementation (300 mg/day) on clinic and 24-h ambulatory blood pressure (BP) in 142 treated hypertensive patients. After 12 weeks, clinic BP decreased whether or not patients were randomized to vitamin E. Ambulatory BP showed no change in systolic BP and a small decrease in diastolic BP (-1.6 mm Hg, 95% confidence intervals from -2.8 to -0.4 mm Hg), approaching statistical significance in comparison to the control group (P = .06). Vitamin E supplementation thus seems to have no clinically relevant effect on BP in hypertensive patients already under controlled treatment.

The vitamin K-antagonism of salicylate and warfarin.

When administered in high dosages, salicylate acts as a vitamin K-antagonist: it induces a decrease of the plasma concentration of the Gla-containing coagulation factors and an accumulation of microsomal substrates for vitamin K-dependent carboxylase in the liver and in the lung. In vitro the drugs inhibit the DTT-dependent reductases which mediate the reduction of vitamin K epoxide and vitamin K quinone. NADH-dependent reductase and vitamin K-dependent carboxylase are not inhibited.

Plasmatic and vascular factors of the hemostatic system in rats receiving an estrogen-progestogen combination.

Treatment of rats for 10 estral cycles with an estrogen-progestogen combination giving 100% infertility triggered a vascular response characterized by increased prostacyclin activity in arterial walls and increased systolic blood pressure. In contrast, plasma fibrinolytic activity and physiological coagulation inhibitors as well as vascular fibrinolytic activity were not changed by this treatment. The same rats tended to have shorter occlusion times of an aortic prosthesis, and could represent a useful model to study the blood-vessel-wall interplay during oral contraceptive treatment.