Original articlePrandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: A randomized controlled trial in patients with type 2 diabetes beginning insulin therapy☆
Introduction
Tight blood glucose control can reduce the risk of microvascular complications in type 2 diabetes (United Kingdom Prospective Diabetes Study Group, 1998). Early insulin therapy may contribute to a correction of the underlying pathogenic abnormalities in patients with type 2 diabetes and improve long-term glycemic control. Thus, many diabetes experts advocate the initiation of insulin therapy earlier in the course of type 2 diabetes than has been common in the past (Campbell & White, 2002).
As shown by Monnier, Lapinski, and Colette (2003) in patients with an HbA1c of <8.5%, 50% of the variance in HbA1c levels is due to the level of postprandial hyperglycemia. There is significant evidence that postprandial hyperglycemia may be associated with an increased risk of cardiovascular or cerebrovascular disease, although controlled interventional studies are not yet available (Gerich, 2003, Hanefeld et al., 1996, Temelkova-Kurktschiev et al., 2000). To date, the highest level of evidence for the importance of postprandial hyperglycemia comes from the large, prospective Diabetes Intervention Study, which followed newly diagnosed patients with type 2 diabetes for 11 years. In this study, poor control of fasting glycemia did not increase the risk of myocardial infarction or mortality, whereas poor control of postprandial glucose was associated with a higher all-cause mortality rate when compared to the age-matched general population (Hanefeld et al., 1996, Hanefeld et al., 1999a). Thus, it has been suggested that diurnal blood glucose variability may represent an independent risk factor for morbidity and mortality of type 2 diabetes (Bonora & Muggeo, 2002).
Insulin analogs exhibit more physiological time-action profiles than human insulins and thus may help achieve more physiological insulin and blood glucose profiles (Heise & Heinemann, 2001). Two types of analogs are currently available—those with a rapid onset and short duration of action and those with a long duration of action. To provide the physiological advantages of rapid-acting insulin lispro in the convenience of a premixed formulation, fixed mixtures containing lispro and a basal component (lispro co-crystallized with protamine, NPL) were developed. They retain both the rapid activity profile of insulin lispro, resulting in better postprandial glycemic control, and the ability to inject closer to meal time (Roach et al., 1999). The long-acting insulin glargine can be injected once daily, most commonly at bedtime (HOE 901/2004 Study Investigators Group, 2003, Rosenstock et al., 2000, Rosenstock et al., 2001, Yki-Järvinen et al., 2000). Glargine provides an essentially peakless basal insulin supply over a 24-h period with single-daily or occasionally twice-daily administration (Heinemann et al., 2000).
There is still considerable debate over which type of insulin substitution is preferred as initial insulin treatment for early type 2 diabetes, or for which patients. This randomized 6-month study compared two different treatment strategies using treatment targets recommended by the ADA. It assessed whether prandial insulin substitution with 3× daily insulin lispro or MidMix (insulin lispro mid mixture) targeted at 2-h postprandial blood glucose levels <10 mmol/l would have a more favorable effect on diabetes control than basal insulin therapy with once-daily insulin glargine targeted at fasting blood glucose (FBG) levels of <7 mmol/l (American Diabetes Association, 2001, American Diabetes Association, 2004).
Section snippets
Subjects
Males or females, 30–75 years of age, were eligible to participate if they met the following criteria: type 2 diabetes mellitus (WHO classification) with a duration of 1–10 years, no insulin treatment during the last 3 months, BMI <40 kg/m2, and HbA1c 6.0–10.5% (measured locally within 4 weeks prior to screening).
Design
This was an open-label, randomized, parallel, three-arm, 24-week study including 19 sites in Germany. The study was conducted according to the Declaration of Helsinki and approved by
Patient disposition and baseline characteristics
Of 162 patients randomized, 159 received at least one dose of study drug (lispro: n=52, MidMix: n=54, glargine: n=53). Overall, 87.4% of patients (139 of 159) completed the study; dropout rates were lowest in the lispro group (lispro 7.7%, MidMix 14.8%, glargine 15.1%). Main reasons for premature discontinuation were violation of inclusion criteria (eight) and personal conflict (eight). Treatment groups were well balanced regarding age, duration of diabetes, prior oral antihyperglycemia
Discussion
This randomized trial compared two alternative strategies for initiating insulin treatment in patients with type 2 diabetes: prandial insulin treatment targeted at the control of 2 h-postprandial glucose (three times daily insulin lispro or lispro MidMix, postprandial glucose target <10 mmol/l) vs. basal insulin treatment focused on fasting glucose control (once-daily insulin glargine, fasting glucose target <7 mol/l). Both strategies achieved their respective blood glucose targets in the
Acknowledgments
We thank all investigators for their commitment and their excellent study performance. We also express our appreciation to Frank Kessler, Lilly Deutschland GmbH, for statistical support.
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This study was supported by grants from Lilly Deutschland GmbH, Bad Homburg, Germany.