Eli Lilly and Company Insulins - A Century of Innovation.

Eli Lilly and Company has played a pivotal role in the development of insulin products since its discovery in 1921. Through their dedication to pharmaceutical innovation, Josiah K. Lilly Sr. and George HA Clowes, in close collaborations with the University of Toronto, made insulin commercially available in 1923. Other innovations include the development and commercialization of the first biosynthetic human insulin, a rapid-acting insulin analog and analog mixtures. Lilly has advanced the field of knowledge with significant efforts toward developing a hepatic preferential basal insulin. Other important insulin projects include the first concentrated rapid-acting insulin analog, clinical studies supporting the use of highly concentrated human insulin, and an advanced clinical development program for an ultra-rapid insulin analog. Lilly's commitment to people affected with diabetes remains strong and will continue into the future through collaborative research, innovative product development and investing in advanced technologies.

The physiological effects of low-intensity neuromuscular electrical stimulation (NMES) on short-term recovery from supra-maximal exercise bouts in male triathletes.

This study investigated the acute effects of NMES on blood lactate (BLa) and performance parameters in trained male triathletes. On three separate days, 13 trained male triathletes performed six 30 s Wingate tests (30 WanT) on a cycle ergometer. Each session consisted of performing 3 × 30 WanT (bouts 1-3) followed by a randomly assigned 30 min recovery intervention of either: (i) passive (seated), (ii) active (cycling at 30% VO(2 max)) or (iii) NMES (1 Hz/500 µs-ON:OFF 2:6 s). The 3 × 30 WanT bouts were then repeated (bouts 4-6) and compared to bouts 1-3 for peak power (PP), mean power (MP) and fatigue index (FI). BLa and heart rate (HR) were recorded at designated time points throughout. Data were analyzed using repeated measures ANOVA with Tukey's honestly significant difference post hoc test. BLa decreased significantly faster during the active recovery intervention (P < 0.001), however, there were no significant differences between interventions for PP (P = 0.217), MP (P = 0.477) and FI (P = 0.234) when the post intervention bouts (4-6) where compared to the pre intervention bouts (1-3). NMES during recovery was not more effective than active or passive recovery for improving subsequent performance. Despite BLa clearing at a significantly faster rate for the active recovery intervention, PP, MP or FI did not improve significantly compared to NMES and passive. In conclusion, NMES does not appear to be more effective than traditional methods for enhancing short-term recovery from supra-maximal exercise bouts in trained male triathletes.

Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes.

AIM: To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. METHODS: This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. RESULTS: Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m2, HbA1c 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA1c was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). CONCLUSIONS: In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA1c was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.

Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes.

AIMS: To compare the glycaemic control of an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily in combination with metformin to that of once-daily insulin glargine plus metformin in patients with Type 2 diabetes inadequately controlled with intermediate insulin, or insulin plus oral agent(s) combination therapy. RESEARCH DESIGN AND METHODS: Ninety-seven patients were randomized in a multicentre, open-label, 32-week crossover study. Primary variables evaluated: haemoglobin A1c (A1c), 2-h post-prandial blood glucose (BG), hypoglycaemia rate (episodes/patient/30 days), incidence (% patients experiencing > or = 1 episode) of overall and nocturnal hypoglycaemia. RESULTS: At endpoint, A1c was lower with the insulin lispro mixture plus metformin compared with glargine plus metformin (7.54% +/- 0.87% vs. 8.14% +/- 1.03%, P < 0.001). Change in A1c from baseline to endpoint was greater with the insulin lispro mixture plus metformin (-1.00% vs. -0.42%; P < 0.001). Two-hour post-prandial BG was lower after morning, midday, and evening meals (P < 0.001) during treatment with the insulin lispro mixture plus metformin. The fasting BG values were lower with glargine plus metformin (P = 0.007). Despite lower BG at 03.00 hours (P < 0.01), patients treated with the insulin lispro mixture plus metformin had a lower rate of nocturnal hypoglycaemia (0.14 +/- 0.49 vs. 0.34 +/- 0.85 episodes/patient/30 days; P = 0.002), although the overall hypoglycaemia rate was not different between treatments (0.61 +/- 1.41 vs. 0.44 +/- 1.07 episodes/patient/30 days; P = 0.477). CONCLUSION: In patients with Type 2 diabetes and inadequate glucose control while on insulin or insulin and oral agent(s) combination therapy, treatment with a twice-daily insulin lispro mixture plus metformin, which targets both post-prandial and pre-meal BG, provided clinically significant improvements in A1c, significantly reduced post-prandial BG after each meal, and reduced nocturnal hypoglycaemia as compared with once-daily glargine plus metformin, a treatment that targets fasting BG.

A comparison of insulin lispro Mix25 and human insulin 30/70 in the treatment of type 2 diabetes during Ramadan.

OBJECTIVE: To compare insulin lispro Mix25 and human insulin 30/70 with regard to their effect on morning and evening postprandial glucose (PPG) control, and on average daily blood-glucose (BG), in patients with Type 2 diabetes who wish to fast during Ramadan. METHOD: Insulin lispro Mix25 and human insulin 30/70 were compared in an open-label, multicenter, randomised, crossover study involving 151 patients. Each treatment period had a duration of 14 days during which the patients self-monitored their BG before and 2 h after the main meals on any 3 days within the last 5 days of each treatment period. RESULTS: The 2 h PPG excursion following the main evening meal after sunset was significantly lower with insulin lispro Mix25 (3.4+/-2.9 mmol/l) compared with human insulin 30/70 (4.0+/-3.2 mmol/l, P=0.007). The evening pre-meal fasting BG values were also lower with insulin lispro Mix25 (7.1+/-2.2 mmol/l) versus human insulin 30/70 (7.5+/-2.6 mmol/l, P=0.034). The average daily BG concentration was 9.5+/-2.4 mmol/l during treatment with insulin lispro Mix25 versus 10.1+/-2.5 mmol/l with human insulin 30/70 given in identical doses (P=0.004). CONCLUSION: When compared with human insulin 30/70, treatment of insulin-requiring Type 2 patients with insulin lispro Mix25 during Ramadan resulted in better average daily glycaemia, and better BG control before and after the evening meal. Insulin lispro Mix25 should be considered as a therapeutic option during Ramadan.

Patient acceptability of a new 3.0 ml pre-filled insulin pen.

The objective of these two studies was to assess patient acceptance and feature preferences of the new Lilly 3.0 ml pre-filled pen. A total of 701 patients with diabetes mellitus, who required insulin, were treated for 4-6 weeks with the pre-filled pen. Patient acceptance and treatment preferences were assessed by a questionnaire completed at the end of the study period. Patients with type 1 or type 2 diabetes mellitus from South Africa (n = 371) and Croatia (n = 330) were enrolled in the study. The mean age was 51.6 years (range: 18-81), and gender was 359 males and 342 females. Prior to the study, patients in South Africa (SA) had used the Novo Actraphane (Novo Nordisk, Bagsvaerd, Denmark) pen set, and patients in Croatia (C) had used NovoPen 1 or 2 (Novo Nordisk, Bagsvaerd, Denmark) (38.8%), NovoPen 3 (Novo Nordisk, Bagsvaerd, Denmark) (28.8%), B-D Pen (Becton-Dickinson, Franklin Lakes, New Jersey, USA) (18.8%), needle/syringe (10.0%), oral hypoglycaemic agents (2.1%), or unknown (1.5%). The new Lilly 3.0 ml pre-filled pen features that were rated by respondents as good to excellent on a five-point rating scale included: cartridge visibility (C = 94%, SA = 83%), ease of dose correction (C = 92%, SA = 85%), dialling of the dose (C = 89%, SA = 81%), turning of the dose knob (C = 84%, SA = 82%) and attaching needles (C = 92%, SA = 78%). Most respondents (C = 78%, SA = 75%) preferred single-unit versus two-unit dosage increments. Overall, 76% of patients in Croatia and 80% in South Africa preferred the Lilly 3.0 ml pre-filled pen to their previous delivery device; 84% and 87% of patients, respectively, would recommend the pen to another patient. Also, the majority of patients in both trials rated the new Lilly 3.0 ml pre-filled pen as being more convenient and easier to use, and indicated that it represented a significant or modest improvement over their previous insulin injection method. The results of this study confirm that the new Lilly 3.0 ml pre-filled pen is widely accepted and preferred by patients using both reusable and pre-filled devices.

Improved postprandial glycemic control with Humalog Mix75/25 after a standard test meal in patients with type 2 diabetes mellitus.

OBJECTIVE: This double-blind study was designed to compare the postprandial glucodynamic profile of Humalog Mix75/25, a new premixed insulin analogue containing 75% neutral protamine lispro and 25% insulin lispro with that of human insulin 70/30 (70% neutral protamine Hagedorn insulin and 30% regular human insulin) in patients with type 2 diabetes mellitus. BACKGROUND: Insulin lispro Mix75/25 (Mix75/25) is the first available insulin formulation in which both the rapid-acting and basal components are insulin analogues. METHODS: This randomized, multicenter, double-blind, crossover study monitored patients' postprandial glucodynamic response to Mix75/25 and human insulin 70/30 (70/30) after a standard test meal. Eighty-four patients with type 2 diabetes participated in this study and were randomly assigned to 1 of 2 treatment sequence groups. Patients received an identical test meal on 4 occasions, completing 2 test meals for each treatment. Equal doses of Mix75/25 or 70/30 were administered 5 minutes before each of the 2 test meals, with doses individualized for each patient. Blood samples were collected for 4 hours after the meal for measurement of plasma glucose. From these plasma glucose measurements, fasting plasma glucose, 2-hour postprandial glucose (2pp), 2-hour postprandial glucose excursion (2pp(ex)), maximum glucose excursion (Gex(max)), the area under the glucose concentration versus time curve from 0 to 4 hours (AUC4), and the area under the glucose excursion versus time curve from 0 to 4 hours (AUCex4) were calculated. RESULTS: Because of significant differences in the baseline fasting plasma glucose levels between Mix75/25 and 70/30 (Mix75/25: 8.9+/-2.2 mmol/L [160.2+/-39.6 mg/dL]; 70/30: 8.6+/-1.9 mmol/L [154+/-34 mg/dL), analyses of the excursion parameters provide a truer comparison of the glucodynamic response between insulin formulations. Mix75/25 resulted in significantly lower values for 2pp(ex) (3.35+/-2.28 vs 4.13+/-2.26 mmol/L), Gex(max) (4.51+/-1.88 vs 5.19+/-1.98 mmol/L), and AUCex4 (8.01+/-7.02 vs 10.6+/-6.47 mmol x h/L) compared with 70/30. CONCLUSIONS: In patients with type 2 diabetes mellitus, premeal injection of Mix75/25 resulted in better postprandial glycemic control than did premeal injection of 70/30 in the 4 hours after a standard meal. Mix75/25 is a valuable option for managing postprandial blood glucose in patients with type 2 diabetes mellitus who require insulin.

Humalog Mix25 offers better mealtime glycemic control in patients with type 1 or type 2 diabetes.

To compare the postprandial glucodynamics of Humalog Mix25, (Humalog Mix75/25 in the US; Mix25), to human insulin 30/70 (Humulin 70/30 in the US; 30/70) in patients with type 1 or type 2 diabetes. Ninety-three patients with type 1 diabetes and 84 patients with type 2 diabetes were evaluated in two separate but identical protocols using a randomized, multicenter, double-blind, crossover design. Patients consumed test meals 5 minutes after equal doses of Mix25 or 30/70. Plasma glucose was measured at baseline and 15 minute intervals for 4 hours after the meal. Two-hour postprandial glucose (2pp), 2-hour glucose excursion (2pp(ex) ), glucose versus time area under the curve 0 to 4 hours (AUC(0-4) ) and glucose excursion area under the curve 0 to 2 and 0 to 4 hours (AUCex(0-2), AUCex(0-4) ) were calculated. For the combined patient population, Mix25 resulted in significantly lower 2pp (12.45 +/- 3.59 vs. 13.47 +/- 3.62 mmol/L; p <0.001), AUC(0-4) (44.45 +/- 12.20 vs. 47.25 +/- 11.97 mmol x h/L; p <0.001), and glucose excursion parameters: 2pp(ex) (3.20 +/- 2.72 vs. 4.40 +/- 2.81 mmol/L; p <0.001), AUCex(0-2) (5.45 +/- 3.15 vs 6.60 +/- 3.13 mmol x h/L; p <0.001), and AUCex(0-4) (7.57 +/- 8.37 vs. 11.02 +/- 8.47 mmol x h/L; p <0.001) compared to 30/70. Further analysis of the treatment by type of diabetes indicated that Mix25 provided nearly identical glucose excursion responses in type 1 and type 2 diabetes up to 2 hours after the test meal, in contrast to 30/70. Pre-meal injection of Mix25 resulted in lower postprandial blood glucose levels compared to 30/70. The postprandial blood glucose response following Mix25 was similar in patients with either type 1 or type 2 diabetes.