OBJECTIVE:This study was designed to compare glycemic control (glycated hemoglobin [A1C] level) with either once-daily basal insulin (BI) (insulin glargine) or preprandial insulin (PPI) (Exubera) [insulin human (recombinant DNA origin)] inhalation powder, Pfizer Inc., New York, NY) in patients with type 2 diabetes mellitus (T2DM) poorly controlled on at least two oral antidiabetes agents (OADs).METHODS:This was a 26-week, open-label, parallel-group, randomized study where 257 patients (mean A1C 8.6%) on OAD treatment for > or = 3 months were treated with either BI (n = 122) or PPI (n = 135). Based on self-monitored blood glucose levels, PPI dose was adjusted before each major meal, whereas BI dose was titrated in the morning or before bedtime. Prestudy OADs were continued, but doses could be modified.RESULTS:At 26 weeks, change from baseline in A1C was greater with PPI (-1.7 vs. -1.4%, P = 0.0389). Numerically, more patients achieved A1C <6.5% (28% vs. 19%) and A1C <7.0% (63% vs. 55%) with PPI compared with BI. PPI had lower postmeal glucose increments, but higher prebreakfast glucose and weight gain (1.1kg), than BI. Mild or moderate hypoglycemic events were more frequent with PPI (6.2 vs. 2.9 events/months), but nocturnal hypoglycemic events were less frequent (22% vs. 30%).CONCLUSIONS:PPI improved postprandial glucose and A1C levels significantly more than BI. More patients achieved A1C targets with PPI, at the expense of more hypoglycemia and body weight gain. These results illustrate the potential benefits and detriments of prandial insulin supplementation in patients with T2DM poorly controlled on OADs alone.

Aim To examine the impact of inhaled human insulin (Exubera (R), EXU) on patient or physician willingness to adopt insulin after oral glucose-lowering agent failure.Methods During a randomized controlled trial in primary, secondary and tertiary care in Europe and North America, 739 patients using >= 2 oral glucose-lowering agents with glycated haemoglobin (HbA(1c)) >= 8.0% were assigned to two treatment groups: Group 1 (standard care with the option of EXU) or Group 2 (standard care only). Standard care included adjusting oral therapy (optimizing current regimen or adding/omitting agents) and/or initiating subcutaneous (s.c.) insulin. The primary endpoint was difference in HbA(1c) between randomized groups at 26 weeks. Secondary outcomes included differences in the rate of uptake of insulin therapy, proportion achieving satisfactory glycaemic control, treatment satisfaction and safety outcomes.Results At baseline, insulin was initiated by more [odds ratio 6.0; 95% confidence interval (CI) 4.2 to 8.8; P < 0.0001] patients in Group 1 (86.2%; 76.7% EXU plus 9.5% s.c.) than Group 2 (50.7%; s.c. insulin only). At 26 weeks, mean (sd) changes in HbA(1c) from baseline were -2.0% (1.2%) and -1.7% (1.3%) in Groups 1 and 2, respectively, a difference of -0.2% (95% CI: -0.1% to -0.4%; P = 0.004). In Group 1, 45% of patients achieved an HbA(1c) <= 7.0% by 26 weeks compared with 39% in Group 2 (P = 0.02).Conclusion The availability of EXU may increase initiation of insulin, thereby contributing to improved overall glycaemic control in patients with Type 2 diabetes inadequately controlled on two or more oral glucose-lowering agents.

A new and regioselective strategy was developed for the preparation of fluorine-18-labeled insulin as a novel positron emission tomography (PET) tracer. [18F]-4-Fluorobenzoic acid (4-18FBA), which was produced in 83 +/- 8% yield (n = 10), through the use of succinimidyl [18F]-4-fluorobenzoate (4-(18)FSB), was conjugated through a short spacer (6-aminohexanoic acid, AHx) to the PheB1 residue of a protected form of insulin. 18FB-AHx-insulin (8b) was repeatedly prepared in practical quantities (10-20 mCi, 370-740 MBq) in good radiochemical yield (9 +/- 5%, n = 9) and in a specific activity of 7.8 mCi/micromol. The final product was characterized by comparing the radioHPLC and radioTLC of 8b with that of the 19F-analogue (19FB-AHx-insulin, 8a) and by analyzing a carrier-added synthesis by mass spectrometry. Dithiothreitol and endoproteinase Glu-C digestion experiments on 8a confirmed that the prosthetic group was in fact conjugated to the PheB1 residue. An insulin receptor (IR) phosphorylation assay using CHO-hIR cells overexpressing recombinant human insulin receptors indicated no statistical difference in the extent of autophosphorylation stimulated by 8a as compared to that for human insulin (EC50 values of 0.82 nM and 1.0 nM, respectively). The stimulation of 2-deoxyglucose uptake in 3T3-L1 mouse adipocytes utilizing 8a versus unmodified human insulin gave similar EC50 values of 0.68 nM and 0.41 nM, respectively. The IC50 values for 8a versus native insulin for the displacement of 125I-insulin from HEK-293 cells were also the same within experimental error (2.6 nM for 8a versus 2.4 nM for unmodified human insulin). These results support the use of the 18F-insulin analogue as a PET tracer for imaging the distribution of insulin in vivo.

Pulmonary insulin delivery is being developed as a more acceptable alternative to conventional subcutaneous administration. In 15 healthy Beagle dogs (average weight 9.3 kg), we compared insulin distribution in arterial, deep venous, and hepatic portal circulation. Dogs received 0.36 units/kg s.c. regular human insulin (n = 6) or 1 mg (2.8 units/kg) or 2 mg (5.6 units/kg) dry-powder human inhaled insulin (n = 3 and 6, respectively). Postinhalation of inhaled insulin (1 or 2 mg), arterial insulin levels quickly rose to a maximum of 55 +/- 6 or 92 +/- 9 microU/ml, respectively, declining to typical fasting levels by 3 h. Portal levels were lower than arterial levels at both doses, while deep venous levels were intermediate to arterial and portal levels. In contrast, subcutaneous insulin was associated with a delayed and lower peak arterial concentration (55 +/- 8 microU/ml at 64 min), requiring 6 h to return to baseline. Peak portal levels for subcutaneous insulin were comparable to those for 1 mg and significantly less than those for 2 mg inhaled insulin, although portal area under the curve (AUC) was comparable for the subcutaneous and 2-mg groups. The highest insulin levels with subcutaneous administration were seen in the deep venous circulation. Interestingly, the amount of glucose required for maintaining euglycemia was highest with 2 mg inhaled insulin. We conclude that plasma insulin AUC for the arterial insulin level (muscle) and hepatic sinusoidal insulin level (liver) is comparable for 2 mg inhaled insulin and 0.36 units/kg subcutaneous insulin. In addition, arterial peak concentration following insulin inhalation is two times greater than subcutaneous injection; however, the insulin is present in the circulation for half the time.

OBJECTIVE:To compare the effects of insulin lispro (LP) and human regular insulin (HR) when given twice daily with NPH insulin on glycemic control (HbA1c), daily blood glucose profiles and rates of hypoglycemia in patients with type 2 diabetes mellitus after failure to respond to sulfonylurea drugs.RESEARCH DESIGN AND METHODS:A 5.5-month randomized, open-label, parallel study of 148 patients receiving either LP (n = 70) or HR (n = 78). Eight-point blood glucose profiles and HbA1c measurements were collected at baseline, 1.5, 3.5 and 5.5 months.RESULTS:Two-hour post-breakfast and 2-hour post-supper blood glucose levels (means [and standard errors]) were significantly lower for LP than for HR at the end point (9.5 [0.4] mmol/L v. 10.9 [0.4] mmol/L and 8.4 [0.4] mmol/L v. 9.7 [0.4] mmol/L, respectively, p = 0.02 in both cases). HbA1c improved from 10.5% (0.2%) (LP) and 10.3% (0.2%) (HR) to 8.0% (0.1%). Hypoglycemia rates were similar during the day; however, there was an overnight trend to reduced rates with LP (0.08 [0.03] episodes/30 d v. 0.16 [0.04] episodes/30 d, p = 0.057). Quality-of life assessment showed significant improvement (p < 0.05) in the diabetes-related worry scale for LP subjects whereas HR subjects slightly worsened.CONCLUSIONS:With traditional twice-daily insulin administration algorithms, LP improves 2-hour postprandial glucose levels, quality of life and overnight hypoglycemia rates while delivering an equivalent level of glycemic control (HbA1c) compared with HR to insulin-naïve patients with type 2 diabetes who require insulin.

A total of 166 patients (102 type 1, 64 type 2) were randomised to insulin lispro (LP) combined with insulin lispro protamine suspension (NPL), an intermediate-acting formulation of LP, or to regular human insulin (HR) combined with human NPH insulin (NPH) in this open-label, parallel study, Insulin doses were similar at endpoint. Blood glucose (BG) measurements (before and two hours after meals, bedtime, 3 a.m.)(mmol/l) were lower with LP/NPL two hours after breakfast (8.84 +/- 0.32 vs 10.29 +/- 0.41, p<0.001), before lunch (6.21 0.20 vs 7.10 +/- 0,31, p=0.016), two hours after the evening meal (10.18 +/- 0.36 vs 7.86 +/- 0,28, p<0.0.001), and at bedtime (7.85 0.28 vs 9.43 +/- 0.40, p=001), HbA(1c) was lower for LP/NPL at endpoint (7.54 +/- 0.11% vs 7.92 +/- 0,10%, p=0.019). There was no difference in hypoglycaemia or insulin antibody levels, LP/NPL resulted in better glycaemic control than HR/NPH without increasing the risk of hypoglycaemia.

OBJECTIVE:To compare human ultralente (UL) insulin with human NPH insulin as basal insulin replacement in patients who use insulin lispro before meals.RESEARCH DESIGN AND METHODS:There were 178 patients with type 1 diabetes who were randomized to receive either human NPH or UL insulin once daily at bedtime in a 1-year double-blind clinical study. Eight-point blood glucose profiles were collected once monthly in the first 4 months, then every 2 months for the remainder of the study. Patients were also asked to perform premeal blood glucose measurements every day throughout the study. If before-supper blood glucose levels consistently exceeded 8 mmol/l despite optimal postprandial control with the lunch dose of insulin lispro, a second dose of basal insulin before breakfast was administered.RESULTS:For the group as a whole, insulin doses before meals and basal insulin doses were similar at baseline. At study's end, meal doses remained the same (30 +/- 1 U/day for UL., 29 +/- 1 U/day for NPH), while basal requirements were somewhat higher for the UL group than the NPH group: 30 +/- 1 U/day vs. 26 +/- 1 U/day, respectively (P < 0.05). The rates of severe hypoglycemia were similar for patients on NPH (0.05 +/- 0.03 per patient every 30 days) and for UL (0.07 +/- 0.04 per patient every 30 days) insulin. There was no significant difference for glycemic control between the NPH and UL groups overall (HbAlc at the end of the study: 7.6 +/- 0.1 vs. 7.7 +/- 0.1%, respectively), and by study's end a similar number of patients in the NPH and the UL groups needed to be switched to twice daily basal insulin (21 and 24%, respectively). Patients requiring twice-daily injections of basal insulin had a longer duration of diabetes (17.8 +/- 1.5 vs. 14.0 +/- 0.8 years, P < 0.05) and a highest baseline HbAlc (8.6 +/- 0.1 vs. 8.0 +/- 0.1%, P < 0.002) and were significantly older (38 +/- 2 vs. 34 +/- 1 years, P < 0.007). Patients who were switched to twice-daily NPH insulin had lower HbAlc levels at study's end compared with those switched to twice-daily UL insulin (7.7 +/- 0.2 vs. 8.2 +/- 0.3%), but this difference was not statistically significant. Distribution of hypoglycemia across the day was also similar in both groups.CONCLUSIONS:UL or NPH insulin, when used as the basal insulin for multiple injection regimens, results in similar glycemic control in patients using insulin lispro before meals. However, in patients who require a second injection of basal insulin, NPH insulin appears to provide lower prebreakfast and prelunch glucose levels compared with UL insulin.

OBJECTIVE People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study. After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 μg/h) to suppress endogenous glucagon, regular insulin (0.15 mU · kg−1 · min−1), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6−2H2]glucose to measure HGP. During the last 2 h, glucagon was infused at 1.5 ng · kg−1 · min−1. Eight nondiabetic people served as control subjects. RESULTS During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7 ± 1.6 vs. 74.8 ± 0.5 pmol/1 after lispro and regular insulin treatment, with plasma glucagon levels of 88.3 ± 1.8 and 83.7 ± 1.5 ng/1 for insulin:glucagon ratios of 2.8 and 3.0, respectively (NS). However, plasma glucose increased to 9.2 ± 1.1 mmol/l after lispro insulin compared with 7.1 ± 0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 ± 2.8 μmol · kg−1 · min−1 after lispro insulin versus 3.1 ± 2.9 μmol · kg−1 · min−1 after regular insulin treatment (P = 0.02). In the control subjects, HGP increased by 10.7 ± 4.2 μmol · kg−1 · min−1 under glucagon infusion. CONCLUSIONS Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.

OBJECTIVE:To determine whether the long-term use of insulin lispro (LP) affects the counterregulatory hormone response to hypoglycemia. RESEARCH DESIGN AND METHODS:Ten patients (age range 26-51 years; ratio of men to women 9:1; BMI 24.9 +/- 0.48; mean HbA1c 7.84 +/- 0.25%) with IDDM, treated with continuous subcutaneous insulin infusion (CSII; Disetronic H-TRON V100) were studied using a double-blind, crossover design. Patients were randomized to LP or human regular insulin (HR) for 3 months and then crossed over to the other insulin for an additional 3 months. All meal boluses were given 0-5 min before breakfast, lunch, and dinner. Counterregulatory hormone responses to a stepped hypoglycemic clamp (consecutive glucose levels in mmol/l: 4.2; 3.5; 2.8, each for 1 h) were evaluated at the end of each treatment period. RESULTS:HbA1c was significantly lower with LP versus HR (7.47 +/- 0.28% vs. 7.9 +/- 0.26%, P = 0.04). The incidence of hypoglycemia per 30 days (capillary blood glucose < 3.0 mmol/l and/or symptoms) during the last month of the study was significantly lower with LP versus HR (8.7 +/- 2.9 vs. 11.8 +/- 2.9, P = 0.03). The total daily insulin dosage was not different in the two treatment periods. There was no episode of severe hypoglycemia or diabetic ketoacidosis. The peak growth hormone, cortisol, glucagon, and epinephrine responses during the same period of hypoglycemia were not different for each treatment period. CONCLUSIONS:The use of LP in CSII results in improved glycemic control and a decrease in the frequency of hypoglycemia without adversely affecting counterregulatory hormone response to hypoglycemia.

PURPOSE This study was undertaken to determine the maximum-tolerated doses of gemcitabine and cisplatin, each given weekly for 3 weeks with a 1-week rest. PATIENTS AND METHODS Patients less than 75 years of age were eligible if they had stage III/IV non-small-cell lung cancer (NSCLC), life expectancy > or = 12 weeks, hemoglobin level > or = 10 g/dL, granulocyte count > or = 2 x 10(9)/L, platelet count > or = 100 x 10(9)/L, hepatic enzymes < or = three times the upper limit of normal, and creatinine concentration < or = 130 mumoles/L. The starting doses for gemcitabine and cisplatin were 1,000 mg/m2 and 25 mg/m2 per week for 3 weeks. At dose level 2, cisplatin was increased to 30 mg/m2/wk for 3 weeks, and thereafter only gemcitabine was increased by 250 mg/m2/wk at each dose level to a maximum of 2,250 mg/m2/wk. RESULTS There were 33 men and 17 women, with a median age of 62 years. Pathology included adenocarcinoma in 35 patients, squamous in eight, large cell in six, and mixed histology in one. Sixteen patients had stage III and 34 had stage IV tumors. The median nadir granulocyte and platelet counts decreased with each dose level, but cycle 1 dose-limiting toxicity (DLT) in > or = two patients was not encountered in cycle 1, even at the highest dose level. Cumulative marrow toxicity was seen at all levels, which resulted in frequent dose reductions or omissions. A mathematic model of all toxicities over time suggested that dose level 4 (cisplatin 30 mg/m2/wk and gemcitabine 1,500 mg/m2/wk) would be the maximum dose at which grade 4 toxicity would be expected in < or = 33% of patients over four cycles. Of 47 assessable patients, 14 achieved a partial response (30%; confidence interval, 17% to 43%). The median duration was 16 weeks and the median survival time was 24 weeks (range, 3.5-64+). CONCLUSION Weekly gemcitabine and cisplatin are active against NSCLC, and the recommended phase II doses are 30 and 1,500 mg/m2/wk for 3 weeks, respectively.

When given at doses of > or = 1,250 mg2 weekly x 3 with a 1-week break, single-agent gemcitabine induces responses in more than 20% of previously untreated patients with non-small cell lung cancer (NSCLC). This study was undertaken to determine the maximum tolerated doses for a 4-week cycle of gemcitabine and cisplatin given in combination weekly x 3 with a 1-week rest. Patients younger than 75 years were eligible if they had stage III/IV NSCLC, life expectancy > or = 12 weeks, hemoglobin > or = 10 g/dL, absolute granulocyte count > or = 2 x 10(9)/L, platelets > or = 100 x 10(9)/L, hepatic enzymes < or = 3 times the upper limit of normal, and serum creatinine < or = 130 mumol/L. The starting doses for gemcitabine and cisplatin were 1,000 mg/m2 and 25 mg/m2 per week x 3, respectively. At dose level 2 cisplatin was increased to 30 mg/m2/week x 3. Thereafter only the gemcitabine was increased, by 250 mg/m2/wk at each dose level, to a maximum of 2,250 mg/m2/wk at dose level 7. The median nadir granulocyte and platelet counts decreased with each dose level, but dose-limiting toxicity in two or more patients was not encountered in the first treatment cycle, even at dose level 7. Cumulative bone marrow toxicity was seen at all dose levels, and this resulted in frequent dose reductions or omissions. Dose delivery was well maintained over time only at dose level 1. Grade 3-4 nonhematologic toxicity was infrequent and rarely dose limiting. An assessment of all toxicities seen during the treatment cycles was undertaken using continual reassessment methodology. This model suggested that dose level 4 (cisplatin 30 mg/m2/wk and gemcitabine 1,500 mg/m2/wk) would be the maximum dose at which grade 4 toxicity would be expected in up to 33% of patients at any time over four treatment cycles. Of 47 patients evaluable for response, partial remission was seen in 14, with an overall response rate of 30% (confidence interval, 17% to 43%). The median duration of response was 16 weeks and the median survival time was 24 weeks (range, 3.5 to 64+ weeks). A phase II trial is planned in which dose level 4 will be evaluated in a larger cohort of patients with NSCLC.

Tabled 1 Dose mg/m2 No. of pts Nadir count ECOG 3/4 toxicity Response PR/evaluable GEM CP Cycle 1 Cycles 1 to 4 gram platelets grans platelets 1000 25 7 3.9 151 43/14 14/0 3/7 1000 30 6 2.1 130 33/0 33/17 2/5 1250 30 7 1.6 87 43/29 50/17 0/7 1500 30 7 2.1 142 29/29 67/33 3/7 1750 30 6 1.2 60 33/0 67/17 2/5 2000 30 9 0.7 73 67/33 46/33 2/9 2250 30 8 1.2 60 61/36 57/25 1/7 Open table in a new tab Response rate was 30% (CI 17 – 43%), median duration 20 weeks. Dose limiting toxicity in Cycle 1 was not seen at any level, but after Cycle 2, cumulative myelotoxicity necessitated frequent dose reductions at high GEM doses. Thus GEM 1500 and CP 30 will be used for Phase II study. Supported by Eli Lilly, Canada. Response rate was 30% (CI 17 – 43%), median duration 20 weeks. Dose limiting toxicity in Cycle 1 was not seen at any level, but after Cycle 2, cumulative myelotoxicity necessitated frequent dose reductions at high GEM doses. Thus GEM 1500 and CP 30 will be used for Phase II study. Supported by Eli Lilly, Canada.