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Insulin Lispro

A Pharmacoeconomic Review of its Use in Diabetes Mellitus

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Abstract

Abstract

Insulin lispro is a recombinant insulin analogue with transposed amino acids (proline and lysine) at positions 28 and 29 near the C-terminus of the B-chain. The most prominent practical advantage of insulin lispro over human soluble insulin lies in its very rapid onset of action. This property allows it to be injected immediately before meals and minimises the demands made on patients with type 1 diabetes mellitus, and those with type 2 disease who require insulin, by the ongoing need for careful meal planning and timing. Numerous clinical studies have shown significant improvements in postprandial glycaemic control, with some evidence of reduced rates of severe or nocturnal hypoglycaemia, relative to conventional human insulin in patients receiving lispro-based insulins

Quality-of-life studies show consistent preferences by patients for and increased treatment satisfaction with insulin lispro over human soluble insulin, particularly with variations of the Diabetes Treatment Satisfaction Questionnaire. Willingness of patients and taxpayers to pay additional costs for insulin lispro or a premixed lispro-based formulation over conventional human insulins, and cost benefits favouring formulary inclusion, have been shown in well designed studies carried out in Australia and Canada. Spanish data suggest cost effectiveness in terms of episodes of severe hypoglycaemia avoided, and preliminary German resource utilisation data indicate cost savings related to reduced hospitalisation and general practice costs, with insulin lispro relative to human soluble insulin.

Conclusions: Insulin lispro and premixed formulations of lispro-based insulins offer quality-of-life improvements relative to conventional human insulins in patients with diabetes mellitus. Participants in well designed studies have expressed a preference for lispro-based insulins and have been shown to be willing to pay for the advantages they offer, and current cost-benefit data favour the inclusion of these insulins in formularies and their reimbursement by third party payers. Further research into the pharmacoeconomic implications of insulin lispro use in the long termis needed, particularly with respect to effects on indirect costs and those associated with complications of diabetes mellitus.

Cost of Illness, Glycaemic Control and Quality of Life in Patients with Diabetes Mellitus

Diabetes mellitus accounts for approximately 8% of total healthcare budgets across developed countries, a figure that is set to increase substantially alongside the global prevalence of this disease during the first quarter of the 21st century (from 4% in 1995 to an estimated 5.4% in 2025)

The cost to healthcare systems of diabetes mellitus is considerable. Comprehensive analyses carried out from a government perspective for the years 1995 and 1997 have shown the annual direct cost of diabetes mellitus in the US to be around $US45 billion. This figure increased to $US98 billion when indirect costs were included for 1997. Two-thirds of all costs were incurred by persons aged 65 years and over. Mean total per capita expenditures in 1997 were $US10 071 for patients with diabetes mellitus and $US2669 for persons without the disease. The direct medical costs associated with type 2 diabetes mellitus were estimated in eight European countries in a study involving more than 7000 patients. The total direct cost of type 2 diabetes mellitus in the eight countries was 29 billion euros annually or 2834 euros per patient per year (1999 values); hospitalisations accounted for 55% of direct costs. In another analysis, production losses attributable to morbidity and premature mortality accounted for 57% of the total annual cost of diabetes mellitus in Sweden in 1994 of 5746 million Swedish kronor (≈$US747 million).

Research published over the past decade has shown an association between improvements in long-term glycaemic control and reduced incidence of microvascular complications in patients with diabetes mellitus. US figures show the annual cost of intensive management aimed at tighter glycaemic control to be two to three times that of conventional therapy in patients with type 1 disease, but results are nevertheless available to indicate that sustained reductions in levels of glycated haemoglobin (HbA1c) are associated with overall healthcare cost savings within 1 to 2 years of improvement.

The importance of quality-of-life considerations in patients with diabetes mellitus has been underlined in particular by a utility value analysis in 292 persons that indicated a willingness on the part of the average participant to trade 12% of remaining life expectancy for freedom from diabetes mellitus. Furthermore, a self-management survey in 2056 respondents showed significantly (p < 0.01) lower quality of life on physical and social functioning scales of the short form (SF)-20 questionnaire in patients with insulin-treated type 2 diabetes mellitus than in those with type 1 diabetes mellitus or those with type 2 diabetes mellitus managed with diet and oral antihyperglycaemic drugs.

Clinical Profile of Insulin Lispro

Randomised clinical studies, most of which were of nonblind and crossover design, have generally shown similar overall long-term glycaemic control (as shown by mean HbA1c values) and fasting blood glucose levels in patients receiving insulin lispro (from 0 to 15 minutes before meals) and those being treated with human soluble insulin (20 to 45 minutes before meals). However, small but statistically significant reductions in mean HbA1c values relative to human soluble or isophane insulins, respectively, have been reported in some studies of insulin lispro or premixed insulin lispro (25%) and neutral protamine lispro (75%) [Mix25].1

Mean 2-hour postprandial blood glucose levels were significantly (p < 0.05) lower with insulin lispro than with human soluble insulin (either in addition to basal intermediate- or long-acting insulin) in the majority of clinical studies of intensive multiple-dose therapy. In addition, patients receiving insulin lispro showed reductions in postprandial blood glucose levels or increases that were significantly (p < 0.05) smaller than with human soluble insulin. A small study in 20 patients with type 1 diabetes mellitus who received insulin lispro for at least 1 year (mean 1.8 years) has indicated long-term maintenance of superiority of insulin lispro over human soluble insulin in terms of postprandial glycaemic profiles. Data from two larger trials also demonstrated better glycaemic control with insulin lispro than human soluble insulin over a 1-year period.

There were no increases relative to human insulins in overall rates of hypoglycaemia in patients receiving lispro-based insulins, with lower incidences of severe or nocturnal hypoglycaemia being noted in some trials.

Two nonblind randomised trials in a total of 314 patients with type 2 diabetes mellitus showed that 4 months of treatment with twice-daily administration of Mix25 achieved greater glycaemic control than glibenclamide (glyburide) 15 mg/day. The incidence of hypoglycaemiawas, however, higher in patients treated with the premixed lispro formulation.

The combination of insulin lispro immediately before meals with glibenclamide 10mg twice daily was associated with decreased mean HbA1c levels relative to bedtime human isophane insulin plus glibenclamide in two parallel-group studies in 554 patients with type 2 diabetes mellitus and secondary sulphonylurea failure. Both trials also indicated significantly (p ≤ 0.05) better postprandial glycaemic control with preprandial insulin lispro plus bedtime human isophane insulin or twice-daily glibenclamide than with glibenclamide plus bedtime human isophane insulin or metformin 1 to 2.5g daily.

Results obtained in children receiving insulin lispro show similar activity relative to human soluble insulin to that noted in adults, and three reports in 246 pregnant women with type 1 diabetes mellitus have linked insulin lispro to improved glycaemic control and reduced risk of hypoglycaemia relative to human soluble insulin in this patient group.

Studies in patients receiving continuous subcutaneous insulin infusion showed significantly (p = 0.047 to 0.004) lower mean HbA1c levels over 2 to 4 months with insulin lispro than with human soluble insulin, with no overall differences in rate of hypoglycaemia. Two-hour postprandial blood glucose levels were consistently lower in patients receiving insulin lispro.

A meta-analysis of eight multicentre studies in 2576 patients with type 1 diabetes mellitus has shown a reduction in overall frequency of severe hypoglycaemia with insulin lispro relative to human soluble insulin. Pooled analysis of ten clinical studies in 3634 patients with type 1 or type 2 diabetes mellitus has shown similar incidences of treatment-emergent adverse events or progression of retinopathy, neuropathy or cardiovascular disease with insulin lispro and human soluble insulin.

Pharmacoeconomic Considerations

Quality of Life in Patients Receiving Insulin Lispro. Increased satisfaction with treatment and improved quality of life with insulin lispro relative to other insulin therapies have been shown in a number of studies with quality of life as a primary or secondary endpoint in patients with diabetes mellitus

Clear preferences for insulin lispro over human soluble insulin, as shown by the Diabetes Treatment Satisfaction Questionnaire (DTSQ), revised Questionnaire on Stress in Diabetes and the Diabetes Quality-of-Life Measure, were noted in three nonblind studies (reported as abstracts) after 284 to 2216 patients with type 1 or type 2 diabetes mellitus were transferred from the latter treatment to the former. In one study in 598 patients, 87.5% expressed a preference for insulin lispro on the grounds of increased freedom with meal timing and increased independence in everyday and physical activities.

Similar findings have been reported in randomised comparisons. DTSQ scores from a Japanese 24-week parallel-group study in 426 patients (preliminary report) showed greater treatment satisfaction (p = 0.023) and reduced frequency of undesirable hypoglycaemia (p < 0.001) with insulin lispro relative to human soluble insulin. A fully reported nonblind crossover study in 52 patients with a history of successful treatment with insulin showed superiority of insulin lispro over human soluble insulin with the DTSQ in its original eight-item form (p = 0.0008) and an extended 20-item version (DTSQ-S) [p = 0.0001] for total satisfaction and all categories of meal-related and correctional use of insulin. A further version of the DTSQ (DTSQ-C), designed for sensitivity to effects of changes in therapy, showed particular improvement (all p = 0.0001 vs human soluble insulin) in satisfaction with current treatment, convenience, flexibility, understanding and controllability of blood glucose levels, and wish to continue with current treatment; preferences not evident with the DTSQ-S (recommendation of treatment to others, predictability of blood glucose levels and recognition/correction of mild hypoglycaemia; p ≤ 0.01) were also noted with the DTSQ-C. No differences between treatments were shown by the Well-Being Questionnaire in this study.

Results from clinical trials with quality of life as a secondary endpoint mostly showed higher levels of treatment satisfaction with insulin lispro than with human soluble insulin. Analysis of results from two nonblind, crossover studies in a total of 942 evaluable patients with type 1 or type 2 diabetes mellitus showed greater (p ≤ 0.001) increases from baseline in mean Diabetes Quality of Life Clinical Trial Questionnaire scores after 3 months for mean treatment flexibility (3.1 vs 0.8) and treatment satisfaction (4.7 vs 0.4) with insulin lispro than with human soluble insulin in patients with type 1 diabetes mellitus.

Willingness to Pay for Insulin Lispro. Well designed and fully reported willingness-to-pay (WTP) analyses have been carried out from the perspectives of Australian patients with diabetes mellitus (insulin lispro vs human soluble insulin; n = 83) and Canadian taxpayers [Mix25 vs premixed 30% human soluble and 70% isophane insulins (human 30/70); n = 80]. Significantly higher proportions of respondents preferred insulin lispro or Mix25 over conventional human insulins in both studies. Australian cost-benefit data showed an incremental benefit of insulin lispro over human soluble insulin (mean WTP) of 37.68 Australian dollars ($A)/month (≈$US23.36/month), with the overall WTP favouring insulin lispro (p < 0.0001) [year of costing not stated; conversion to US dollars at 30 June for year of study publication].

The net annual cost benefit of insulin lispro was $A381.84/patient (≈$US236.74/patient), which indicated that the drug should be considered for inclusion in Australian formularies. The net mean monthly WTP value for Mix25 was 35.28 Canadian dollars ($Can) for 1999 (≈$US23.99). The net annual cost benefit of $Can255 (≈$US173.40) indicated eligibility for consideration for formulary inclusion.

Additional data (abstract available) from 69 Australian patients with type 2 diabetes mellitus showed an overall monthly WTP for Mix25 over human 30/70 of $A95.62 (≈$US57.37) [year of costing not stated; conversion to US dollars at 30 June for year of study publication], with a total incremental benefit per patient of $A82.14/month (≈$US49.28/month).

Cost-Effectiveness and Other Studies. Two reports of Spanish cost-effectiveness studies in patients with type 1 diabetes mellitus are available. One of these (published as an abstract) showed, relative to human soluble insulin, a cost per episode of severe hypoglycaemia avoided by use of insulin lispro of $US60 per 100 patient-years on the basis of results of one clinical trial, and a cost reduction of approximately $US129 per episode avoided per 100 patient-years on the basis of results of another (year of costing not stated). The other cost-effectiveness analysis (30 patients participating in a nonblind, crossover study) showed excess costs per 1% reduction in HbA1c level relative to human soluble insulin of $US0.85 and $US0.34 per day of treatment for insulin lispro plus 15 to 20% isophane insulin and insulin lispro alone, respectively (conversion from Spanish pesetas at January 2000).

Retrospective 1-year resource utilisation data from a German database indicated an overall annual cost saving, linked to reduced hospitalisation and general practice treatment costs, of 468 Deutschmarks per patient (≈$US229) [from a statutory health insurer’s perspective] relative to human soluble insulin in patients receiving insulin lispro (year of costing and size of database not stated in the abstract available; conversion to US dollars at 30 June for year of study publication).

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Christopher J. Dunn & Greg L. Plosker

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  1. Christopher J. Dunn
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  2. Greg L. Plosker
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Correspondence to Greg L. Plosker.

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Mix25 is used throughout the manuscript as a ‘generic’ term for this combination. In the US, this combination is marketed as Humalog® Mix 75/25™, while in the UK it is marketed as Humalog® Mix25™. Trade names are provided here for identification purposes only and do not indicate product endorsement.

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Dunn, C.J., Plosker, G.L. Insulin Lispro. Pharmacoeconomics 20, 989–1025 (2002). https://doi.org/10.2165/00019053-200220140-00004

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