Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month extension.

AIMS: To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) over 12 months of treatment in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (OADs). METHODS: EDITION 2 (NCT01499095) was a randomized, 6-month, multicentre, open-label, two-arm, phase IIIa study investigating once-daily Gla-300 versus Gla-100, plus OADs (excluding sulphonylureas), with a 6-month safety extension. RESULTS: Similar numbers of participants in each group completed 12 months of treatment [Gla-300, 315 participants (78%); Gla-100, 314 participants (77%)]. The reduction in glycated haemoglobin was maintained for 12 months with both treatments: least squares (LS) mean (standard error) change from baseline -0.55 (0.06)% for Gla-300 and -0.50 (0.06)% for Gla-100; LS mean difference -0.06 [95% confidence interval (CI) -0.22 to 0.10)%]. A significant relative reduction of 37% in the annualized rate of nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia was observed with Gla-300 compared with Gla-100: rate ratio 0.63 [(95% CI 0.42-0.96); p = 0.031], and fewer participants experienced ≥1 event [relative risk 0.84 (95% CI 0.71-0.99)]. Severe hypoglycaemia was infrequent. Weight gain was significantly lower with Gla-300 than Gla-100 [LS mean difference -0.7 (95% CI -1.3 to -0.2) kg; p = 0.009]. Both treatments were well tolerated with a similar pattern of adverse events (incidence of 69 and 60% in the Gla-300 and Gla-100 groups). CONCLUSIONS: In people with type 2 diabetes treated with Gla-300 or Gla-100, and non-sulphonylurea OADs, glycaemic control was sustained over 12 months, with less nocturnal hypoglycaemia in the Gla-300 group.

One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12-month randomized trial, including 6-month extension.

AIMS: To evaluate the maintenance of efficacy and safety of insulin glargine 300 U/ml (Gla-300) versus glargine 100 U/ml (Gla-100) in people with type 2 diabetes mellitus (T2DM) using basal plus meal-time insulin for 12 months in the EDITION 1 trial. METHODS: EDITION 1 was a multicentre, randomized, open-label, two-arm, phase IIIa study. Participants completing the initial 6-month treatment period continued to receive Gla-300 or Gla-100, as previously randomized, once daily for a further 6-month open-label extension phase. Changes in glycated haemoglobin (HbA1c) and fasting plasma glucose concentrations, insulin dose, hypoglycaemic events and body weight were assessed. RESULTS: Of 807 participants enrolled in the initial phase, 89% (359/404) assigned to Gla-300 and 88% (355/403) assigned to Gla-100 completed 12 months. Glycaemic control was sustained in both groups (mean HbA1c: Gla-300, 7.24%; Gla-100, 7.42%), with more sustained HbA1c reduction for Gla-300 at 12 months: least squares mean difference Gla-300 vs Gla-100: HbA1c -0.17 [95% confidence interval (CI) -0.30 to -0.05]%. The mean daily basal insulin dose at 12 months was 1.03 U/kg for Gla-300 and 0.90 U/kg for Gla-100. Lower percentages of participants had ≥1 confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemic event with Gla-300 than Gla-100 at any time of day [24 h; 86 vs 92%; relative risk 0.94 (95% CI 0.89-0.99)] and during the night [54 vs 65%; relative risk 0.84 (95% CI 0.75-0.94)], while the annualized rates of such hypoglycaemic events were similar. No between-treatment differences in adverse events were apparent. CONCLUSION: During 12 months of treatment of T2DM requiring basal and meal-time insulin, glycaemic control was better sustained and fewer individuals reported hypoglycaemia with Gla-300 than with Gla-100. The mean basal insulin dose was higher with Gla-300 compared with Gla-100, but total numbers of hypoglycaemic events and overall tolerability did not differ between treatments.

New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3).

AIMS: To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with that of glargine 100 U/ml (Gla-100) in insulin-naïve people with type 2 diabetes using oral glucose-lowering drugs. METHODS: The EDITION 3 study was a multicentre, open-label, parallel-group study. Participants were randomized to Gla-300 or Gla-100 once daily for 6 months, discontinuing sulphonylureas and glinides, with a dose titration aimed at achieving pre-breakfast plasma glucose concentrations of 4.4-5.6 mmol/l (80-100 mg/dl). The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to month 6. The main secondary endpoint was percentage of participants with ≥1 nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia from week 9 to month 6. Other measures of glycaemia and hypoglycaemia, weight change and insulin dose were assessed. RESULTS: Randomized participants (n = 878) had a mean (standard deviation) age of 57.7 (10.1) years, diabetes duration 9.8 (6.4) years, body mass index 33.0 (6.7) kg/m(2) and HbA1c 8.54 (1.06) % [69.8 (11.6) mmol/mol]. HbA1c levels decreased by equivalent amounts with the two treatments; the least squares mean difference in change from baseline was 0.04 [95% confidence interval (CI) -0.09 to 0.17] % or 0.4 (-1.0 to 1.9) mmol/mol. Numerically fewer participants reported ≥1 nocturnal confirmed (≤3.9 mmol/l) or severe hypoglycaemia from week 9 to month 6 [relative risk (RR) 0.89 (95% CI 0.66 to 1.20)] with Gla-300 versus Gla-100; a significantly lower risk of hypoglycaemia with this definition was found over the 6-month treatment period [RR 0.76 (95% CI 0.59 to 0.99)]. No between-treatment differences in adverse events were identified. CONCLUSIONS: Gla-300 is as effective as Gla-100 in reducing HbA1c in insulin-naïve people with type 2 diabetes, with lower hypoglycaemia risk.

A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes.

AIMS: The aim of the trial was to compare the efficacy and safety of the new, long-acting basal insulin, insulin glargine (LANTUS(R)), with NPH human insulin, each administered in a combination regimen with oral antidiabetic drugs in patients with Type 2 diabetes. METHODS: In a multicentre, open, randomised study, 570 patients with Type 2 diabetes, aged 34 - 80 years, were treated for 52 weeks with insulin glargine or NPH insulin given once daily at bedtime. Previous oral antidiabetic therapy was continued throughout the study. RESULTS: There was a clinically relevant decrease in glycosylated haemoglobin (GHb) values from baseline to endpoint with both drugs (insulin glargine: - 0.46 %; NPH insulin: - 0.38 %; p = 0.415); also, this difference was statistically significant in the subgroup of overweight patients with BMI > 28 kg/m 2 (insulin glargine: - 0.42 %, NPH insulin: - 0.11 %; p = 0.0237). Over the entire treatment period, NPH insulin-treated patients (41 %) and insulin glargine-treated patients (35 %) experienced a similar level of symptomatic hypoglycaemia. A statistically significant difference was observed in the number of patients treated with NPH insulin who reported at least one episode of nocturnal hypoglycaemia compared with those treated with insulin glargine in the overall population and in the overweight subgroup (overall: 24 % vs. 12 %, p = 0.002; overweight: 22.2 % vs. 9.5 %, p = 0.0006), using the Cochran-Mantel-Haenszel test. These differences were most pronounced in insulin-naïve and overweight (BMI > 28 kg/m 2) sub-groups. The incidence of adverse events was similar for the two treatments. CONCLUSIONS: This study demonstrated that insulin glargine is as effective as NPH insulin in achieving glycaemic control in patients with Type 2 diabetes, and is associated with fewer episodes of symptomatic hypoglycaemia, particularly nocturnal episodes.

Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group.

OBJECTIVE: Available basal insulin formulations do not provide a constant and reliable 24-h insulin supply. We compared the efficacy and safety of glargine (a long-acting insulin analog) and NPH insulins in insulin-naive type 2 diabetic patients treated with oral antidiabetic agents. RESEARCH DESIGN AND METHODS: There were 426 type 2 diabetic patients (age 59 +/- 9 years, BMI 28.9 +/- 4.3 kg/m2, mean +/- SD) with poor glycemic control on oral antidiabetic agents randomized to treatment for 1 year with bedtime insulin glargine or bedtime NPH insulin. Oral agents were continued unchanged. The fasting blood glucose (FBG) target was 6.7 mmol/l (120 mg/dl). RESULTS: Average glycemic control improved similarly with both insulins (HbA(1c), [reference range <6.5%] 8.3 +/- 0.1 vs. 8.2 +/- 0.1% at 1 year, glargine vs. NPH, mean +/- SEM, P < 0.001 vs. baseline for both). However, there was less nocturnal hypoglycemia (9.9 vs. 24.0% of all patients, glargine vs. NPH, P < 0.001) and lower post-dinner glucose concentrations (9.9 +/- 0.2 vs. 10.7 +/- 0.3 mmol/l, P < 0.02) with insulin glargine than with NPH. Insulin doses and weight gain were comparable. In patients reaching target FBG, HbA(1c) averaged 7.7 and 7.6% in the glargine and NPH groups at 1 year. CONCLUSIONS: Use of insulin glargine compared with NPH is associated with less nocturnal hypoglycemia and lower post-dinner glucose levels. These data are consistent with peakless and longer duration of action of insulin glargine compared with NPH. Achievement of acceptable average glucose control requires titration of the insulin dose to an FBG target < or =6.7 mmol/l. These data support use of insulin glargine instead of NPH in insulin combination regimens in type 2 diabetes.

In-vitro activity of cefpirome against isolates from patients with urinary tract, lower respiratory tract and wound infections.

The in-vitro activity of cefpirome, a new injectable cephalosporin, was compared with that of several other antibiotics against bacterial isolates from hospitalized patients with lower respiratory tract infections, urinary tract infections and wound infections. Minimum inhibitory concentrations were determined for 874 strains against 16 antibiotics using a microtitration technique. Cefpirome showed a very broad spectrum of activity against most pathogens tested. The spectrum included organisms such as Staphylococcus spp., enterococci, Enterobacter spp., and Pseudomonas spp. which are frequently resistant to third generation cephalosporins.

Comparison of clinical response to cefpirome treatment and minimum inhibitory concentration of causative isolates. Microbiological and Clinical Study Groups.

Three hundred and forty-five clinical isolates from patients treated with cefpirome were studied using an MIC methodology to develop tentative breakpoints for cefpirome, and to correlate clinical success with in-vitro susceptibility. No relationship between elimination, persistence and MIC of potential pathogens was found. There was, however, a close relationship between clinical cure and improvement and eradication of causative organisms. Based on the data, tentative breakpoints of less than 4 mg/L for sensitive and greater than 16 mg/L for resistance, at a cefpirome dose of 2.0 g bid or 1.0 g bid for urinary tract infection, are suggested.

Haemostasis during treatment with ciprofloxacin.

The effects of ciprofloxacin, a new quinolone derivative with high activity on gram-negative aerobic bacteria and gram-positive cocci, on haemostasis were investigated in 11 healthy volunteers. No influence on platelet function was detectable. In some cases a slight reduction in antithrombin III activity was observed at the end of the therapy. No other changes were evident in the plasma coagulation parameters.

[Rotation angioplasty--a new procedure for reopening and dilating blood vessels. Experimental findings]. / Rotationsangioplastik--ein neues Verfahren zur Gefässwiedereröffnung und -erweiterung. Experimentelle Befunde.

16 fresh postmortem specimens of human femoral and popliteal arteries with severe atherosclerosis were removed and angiography was performed. Eight vessels were completely occluded and eight showed stenoses of up to 60%. All occluded vessels were heavily calcified. The duration of occlusion, estimated according to the patient's history, ranged from 1 to 2 years. In one case, a duration of 18 months was documented by angiography. The lengths of the occlusions were between 5 and 12 cm. A rotating catheter was introduced through a 9F guiding catheter. All stenosed vessels were passed and seven out of eight occluded vessels, in which passage was not possible using conventional wires, were successfully reopened at low speed rotation of 200 rpm. Angiography, as well as histology, showed no perforation, and angioscopy revealed a smooth surface of the new channel. In three vessels this new channel was dilated with a balloon catheter and in one with an elastic element under rotation. It is concluded that with the new technique it is possible to reopen totally occluded human arteries which cannot be passed by conventional methods.

Haemostasiological parameters as risk factor for new arterial occlusions in diabetics.

PARD is a prospective study sponsored by the German Research Council with the aim to establish if spontaneously enhanced platelet aggregation or changes of other hemostatic variables are risk factors for new vascular occlusions in diabetic patients. 363 diabetics (aged 45-65, 232 men, 131 women) have been observed for at least 5 years. Of the 232 men, 53 were on diet, 104 on oral antidiabetic agents and 75 on insulin. Of 131 women 16 were on diet, 46 on oral antidiabetic drugs and 69 on insulin. At entry a medical history was obtained and clinical examinations and laboratory tests were performed. Hemostatic tests and clinical examinations were repeated at 3 month's intervals. The life status was followed for all patients with the exception of 2. Until December 31, 1984, 42 patients had died, 23 from cardiovascular disease and 19 from other causes. 13 patients suffered a myocardial infarction, 11 a stroke and 53 a peripheral arterial occlusion. The occurrence of new vascular occlusions was significantly higher in men with enhanced spontaneous platelet aggregation measured by PAT III. This was not the case for women. Other hemostatic parameters with some relation to cardiovascular complications, again only in men, were fibrinogen, von Willebrand factor together with some established risk factors as triglycerides and hypertension.

Spontaneous platelet aggregation and coagulation parameters as risk factors for arterial occlusions in diabetics. Results of the PARD-study.

PARD is a prospective study sponsored by the German Research Council with the aim to establish whether spontaneously enhanced platelet aggregation or changes of other hemostatic parameters are risk factors for new vascular occlusions in diabetic patients. 363 diabetic patients (aged 45-65, 232 men, 131 women) were observed for 5 years. Of the 232 men, 53 were on diet, 104 on oral antidiabetic drugs and 75 on insulin. Of 131 women 16 were on diet, 46 on oral antidiabetic drugs and 69 on insulin. At entry clinical examination and laboratory tests were performed, covering the known risk factors for cardiovascular complications. Hemostatic tests and clinical examination were performed at 3 months' intervals. The life status was followed for all patients. Endpoints were carefully defined. Until December 31, 1984, 42 patients died, 23 from cardiovascular disease and 19 from other causes. 13 patients suffered a myocardial infarction, 10 a stroke and 53 peripheral arterial occlusions. The occurrence of new vascular occlusions was significantly higher in those men with enhanced spontaneous platelet aggregation measured by PAT III angle alpha above 40 degrees at entry as compared to those with lower values. This was not the case for women. Other hemostatic parameters, which had also some relation to cardiovascular complications, in men were fibrinogen and F. VIII R:Ag. Established risk factors for which a significant relation to cardiovascular complications was observed in this study, were smoking, duration of diabetes, diastolic blood pressure, cholesterol, triglycerides and also HbA1. The results of the PARD-study have verified the hypothesis that spontaneous aggregation is a major risk factor for future vascular occlusions in diabetic men. They also lead to the hypothesis that high levels of F. VIII R:Ag and fibrinogen are further indicators of progressive vascular disease and may be useful as predictors of new vascular occlusions in combination with such established risk factors as smoking, duration of diabetes, diastolic blood pressure, cholesterol, and triglycerides.

[Hemostatic parameters influenced by imipenem/cilastatin]. / Hämostaseologische Parameter unter dem Einfluss von Imipenem/Cilastatin.

Seven patients were treated for bacterial infections with imipenem/cilastatin. Imipenem is a new broad-spectrum beta-lactam antibiotic with antimicrobial activity against gram-positive and gram-negative bacilli. Before and during treatment parameters of blood coagulation and platelet function were studied. Blood coagulation was not influenced by the antibiotic. But there was a temporary inhibition of collagen-induced platelet aggregation during the first days of treatment. No clinical signs of enhanced spontaneous bleeding tendency were observed.

[Thrombocyte function and plasma coagulation following poisoning with organophosphates]. / Thrombozytenfunktion und plasmatische Gerinnung nach Intoxikation mit Organophosphaten.

In nine patients suffering from organophosphate intoxication, platelet function and blood coagulation parameters were investigated. Thrombocyte function was impaired in all patients, characterized by a diminished platelet shape change. Platelet shape change was also inhibited in rats and after oral administration of 10 mg/kg parathion. Thrombocytopenia and coagulation abnormalities (diminished fibrinogen, plasminogen and anti-thrombin III) were more pronounced in cases with severe intoxication. In five of nine patients a marked bleeding tendency was observed. The bleeding tendency in organophosphate intoxication is probably mainly caused by the defective platelet function. Patients with this intoxication should receive heparin only for special indications; haemoperfusion is of doubtful value since this procedure may itself produce haemostatic defects.