Rom J Intern Med.
2003;41(2):153-62.
Humalog Mix 25 in patients with type 2 diabetes which do not achieve
acceptable glycemic control with oral agents: results from a phase III,
randomized, parallel study.
Tirgoviste CI, Strachinariu R, Farcasiu E, Milicevic Z, Teodorescu
G.
N.Paulescu Institute of Diabetes and Metabolic Diseases, 5-7, Ion
Movila Str., Bucharest, Romania.
BACKGROUND: Humalog Mix 25 (Mix 25) is a premixed insulin mixture of
25% lispro and 75% neutral protamine lispro. Insulin lispro is an analog
of human insulin. It is created when the amino acids at positions 28 and
29 of the B-chain of insulin are reversed. The natural sequence in human
insulin at this position is proline at B28 and lysine at B29. The pharmacokinetic
and pharmacodynamic profiles of insulin lispro indicate that it is more
rapid acting, and therefore more physiological mealtime insulin than regular
human insulin. OBJECTIVE: Primary objective of this study was to compare
twice daily treatment with insulin lispro low mixture (Mix 25) to oral
treatment with glibenclamide in patients with type 2 diabetes, with respect
to the mean 2-hour postprandial blood glucose excursions after breakfast
and dinner. SECONDARY OBJECTIVES: to compare the two treatments with regard
to the following: hemoglobin A1c, fasting blood glucose, pre-dinner blood
glucose, frequency of hypoglycemia, body weight, treatment satisfaction
(by questionnaire). METHODS: The study described is a randomized, open-label,
parallel group comparison of two treatment regimens in patients with type
2 diabetes. The study included two periods. The lead-in period lasted
10 +/- 7 days, all patients were taking glibenclamide. The treatment period
lasted 16 weeks. Patients were randomized to receive either glibenclamide
15 mg daily or switch to Mix 25 before breakfast and dinner. Study design
is illustrated in Fig. 1. Glycemic control was assessed by glycosylated
hemoglobin (HbA1c) measurements, 4-point self monitoring blood glucose
profiles, and patient reported hypoglycemia. One treatment satisfaction
questionnaire (Appendix 1) was completed by each participant. RESULTS:
175 patients were included from the two participating countries (Romania--100
patients and Russia--75 patients). 85 were randomized to receive Mix 25
and 90 to glibenclamide arm. 172 patients were included in the efficacy
analysis. Baseline patient characteristics did not show any differences
between treatment groups for any of the demographic (age, gender, height,
body weight, body mass index) or efficacy parameters (HbA1c or self monitored
BG values). The mean age was 59.5 +/- 8.2 years, and 35.5% (61/172) were
men. The mean body mass index was 27.2 kg/m2. The mean duration of type
2 diabetes was 10.2 +/- 6.6 years, and the mean duration of sulfonylurea
treatment was 5.8 +/- 5.9 years. The mean HbA1c and fasting blood glucose
levels were 10.07 +/- 1.4% and 11.6 +/- 2.8 mmol/L, respectively, in the
glibenclamide group and 9.85 +/- 1.2% and 12.2 +/- 2.9 mmol/L, respectively,
in the Mix 25 group. At the end point, all efficacy parameters were better
improved in Mix 25 group (HbA1c, fasting blood glucose, 2-hour postprandial
blood glucose). Mean HbA1c was significantly lower in the Mix 25 group
than in the GB group (Mix 25, 8.5% +/- 1.3%; GB, 9.4 +/- 1.8%; P = 0.001).
For all self-monitored blood glucose values (Fig. 2) a larger decrease
from baseline was observed in the Mix 25 group: -1.4% versus -0.7% for
HbA1c, (P = 0.004); -2.8 mmol/L versus -1.1 mmol/L for fasting blood glucose,
(P < 0.01); -5.1 mmol/L versus -1.7 mmol/L for the morning 2-hour postprandial
blood glucose, (P < 0.001); -2.2 mmol/L versus -0.8 mmol/L for the
evening preprandial blood glucose, (P < 0.05); and 4.4 mmol/L versus
-1.5 mmol/L for the evening 2-hour postprandial blood glucose, (P <
0.001). Percentage of patients experiencing at least 1 episode of hypoglycemia
was--as predicted--higher in the Mix 25 group (44.7% versus 10.3%; P =
0.01). Patients expressed more satisfaction with Mix 25 than with GB,
as measured by the weighted combined score on a treatment satisfaction
questionnaire (2.0 +/- 1.3 vs 0.7 +/- 1.3). CONCLUSIONS: When glycemic
control can no longer be achieved by oral antidiabetic agents, treatment
with insulin should be considered as the next therapeutic option. Mix
25 provided good overall glycemic control, as well as patient treatment
satisfaction.
IEEE Trans Biomed Eng. 2005 Jan;52(1):3-12.
Insulin kinetics in type-I diabetes: continuous and bolus delivery
of rapid acting insulin.
Wilinska ME, Chassin LJ, Schaller HC, Schaupp L, Pieber TR, Hovorka
R.
Department of Paediatrics, University of Cambridge, Cambridge, CB2
2QQ, UK. mew37@medschl.cam.ac.uk
We investigated insulin lispro kinetics with bolus and continuous subcutaneous insulin infusion (CSII) modes of insulin delivery. Seven subjects with type-1 diabetes treated by CSII with insulin lispro have been studied during prandial and postprandial conditions over 12 hours. Eleven alternative models of insulin kinetics have been proposed implementing a number of putative characteristics. We assessed 1) the effect of insulin delivery mode, i.e., bolus or basal, on the insulin absorption rate, the effects of 2) insulin association state and 3) insulin dose on the rate of insulin absorption, 4) the remote insulin effect on its volume of distribution, 5) the effect of insulin dose on insulin disappearance, 6) the presence of insulin degradation at the injection site, and finally 7) the existence of two pathways, fast and slow, of insulin absorption. An iterative two-stage parameter estimation technique was used. Models were validated through assessing physiological feasibility of parameter estimates, posterior identifiability, and distribution of residuals. Based on the principle of parsimony, best model to fit our data combined the slow and fast absorption channels and included local insulin degradation. The model estimated that 67(53-82)% [mean (interquartile range)] of delivered insulin passed through the slow absorption channel [absorption rate 0.011(0.004-0.029) min(-1)] with the remaining 33% passed through the fast channel [absorption rate 0.021(0.011-0.040) min(-1)]. Local degradation rate was described as a saturable process with Michaelis-Menten characteristics [VMAX = 1.93(0.62 - 6.03) mU min(-1), KM = 62.6(62.6 - 62.6) mU]. Models representing the dependence of insulin absorption rate on insulin disappearance and the remote insulin effect on its volume of distribution could not be validated suggesting that these effects are not present or cannot be detected during physiological conditions.
Value Health. 2004 Jul-Aug;7(4):442-54.
Patient preference and willingness-to-pay for Humalog Mix25 relative
to Humulin 30/70: a multicountry application of a discrete choice experiment.
Aristides M, Weston AR, FitzGerald P, Le Reun C, Maniadakis N.
M-TAG Limited, London, England, UK. maristides@m-tag.net
OBJECTIVES: To assess preference and willingness-to-pay (WTP) for the
insulin mixture Humalog Mix25 relative to Humulin 30/70, from the patients'
perspective, the relative importance of individual treatment attributes
was also determined. Differences among five European countries were investigated.
METHODS: Two hundred and ninety patients with type 2 diabetes were recruited
from five European countries. Of these, 235 were suitable for inclusion
in the analysis. Their mean age was 51.3 years and, on average, patients
had had diabetes for 11 years. A discrete-choice conjoint analysis was
conducted using face-to-face interviews. Treatment attributes, such as
timing of injections around meals, 2-hour postprandial control, effect
of prandial dosing, frequency of nocturnal hypoglycemia, and cost, and
levels were derived after a systematic review of all published comparative
clinical trial data. Meta-analyses were undertaken where appropriate.
RESULTS: Ninety percent (95% CI 86-93%) of patients would choose Humalog
Mix25 over Humulin 30/70, at the same cost. On average, European subjects
were willing to pay 111 euros per month more for Humalog Mix25 (95% CI
86.71-156.91 euros). The primary driver was the reduced risk of nocturnal
hypoglycemic events, contributing 49% of WTP. The convenience of dosing
immediately before the meal contributed 37%. Preference results were similar
in all five countries, although WTP and sensitivity to increasing cost
both varied. CONCLUSIONS: Patients in all countries showed a preference
and WTP for Humalog Mix25 over Humulin 30/70. The main drivers of patient
WTP may be of interest to pharmaceutical prescribers, manufacturers, and
reimbursement agencies.
