The results of the Diabetes Control and Complications Trial (DCCT) demonstrated unequivocally that intensive insulin therapy to maintain good glycaemic control could prevent the development of microvascular complications in insulin-dependent diabetes (IDDM), and slow down the progression of these complications where they were already established.^l Efforts to reproduce in clinical practice the impressive levels of control which prevented complications in the DCCT, without increased frequency of hypoglycaemia, have focussed attention on the optimisation of insulin delivery systems. 

Conventional insulin therapy is is unable to mimic physiological insulin secretion. The relatively slow rate of absorption of standard soluble insulins obliges the patient to inject insulin 15-30 minutes prior to meals so that peak insulin action will coincide with the postprandial rise in blood glucose. In addition the 4-6 hour duration of insulin action produces high pre-prandial plasma insulin levels, increasing the risk of hypoglycaemia. Intensive therapy in the DCCT was associated with a threefold increase in the incidence of severe hypoglycaemia¹; this increased risk of hypoglycaemia has been identified by patients as a serious impediment to their willingness to attempt the glycaemic goals which are now proven to prevent complications.²

Lispro insulin

The insulin analogue lispro, recently launched in Ireland, may address some of the shortcomings of conventional short-acting insulins. Lispro is a genetically engineered insulin molecule in which the amino acids proline and lysine have been transposed at positions 28 and 29 on the C terminal end of the B chain, such that it dissociates rapidly into easily-absorbable single molecules after subcutaneous injection.³ It is more rapidly absorbed after subcutaneous injection than soluble insulin, reaching higher, earlier peak plasma insulin concentrations³ and producing lower post prandial blood glucose concentrations.⁴ The rapid clearance of lispro is associated with lower pre-prandial insulin concentrations and a lower incidence of mild hypoglycaemia, particularly at night.⁴ Lispro has also been shown to produce significantly less hypoglycaemia if exercise is taken 2-3 hours after eating.⁵

The effects of lispro on overall glycaemic control are less clear cut. In large crossover trials in both IDDM^4-6 and non-insulin dependent diabetes (NIDDM),^6,7 mean HbA1c levels were comparable to those on soluble insulin. An open study of the transfer of patients from regular soluble insulin to lispro as part of a multiple injection regimen, did show improved glycaemic control, but the absence of a control group weakened the data.⁸ Lispro did however produce better glycaemic control than regular soluble insulin, without increasing the risk of hypoglycaemia, in a study comparing use of the two insulins in continuous subcutaneous infusion pumps.⁹

Favourable outcomes

There seem to be few drawbacks to lispro insulin. The observed decrease in mild hypoglycaemia in the published studies may relate to the higher preprandial blood glucose concentrations on lispro therapy. Tightened preprandial glycaemic control may cancel out the reduction in hypoglycaemia reported in the literature, but this uncertainty needs more experience of the drug in clinical practice. Some patients taking lispro report marked preprandial hyperglycaemia if there is a large gap between meals, which can be reduced by increasing basal insulin doses. There was an overall increase in basal insulin reported in the lispro limb of one study⁴ and a small proportion of patients require twice daily isophane insulin to overcome this problem. 

Convenience benefits

The evidence from the available research studies shows that lispro is a safe, convenient alternative to conventional soluble insulins, which causes fewer hypoglycaemic reactions. It is too early, however, to suggest that lispro will provide DCCT standards of good glycaemic control without unacceptable hypoglycaemia; longer, prospective, randomised studies and more clinical experience are required. There is no indication therefore, for wholesale transfer of patients from conventional insulin to lispro. Patient preference may, however, drive prescribing, as the ability to inject insulin immediately prior to meals is seen as a huge advantage, particularly by those on a multiple injection regimens. One large study showed significant improvement in treatment satisfaction and flexibility with lispro compared with soluble insulin¹⁰ and 74% of patients completing the IOAG study elected to continue with lispro on cessation of the study.⁴ Although the therapeutic role of lispro in the treatment of diabetes remains to be established, there are clear convenience benefits to the patient and it is a welcome addition to the range of insulins currently available. 
Chris Thompson,
Department of Diabetes,
Beaumont Hospital,
Dublin 9
References

1. The Diabetes Control and Complications Trial Research Group. The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 1993;329:977-986. 
2. Thompson CJ, Cummings F, Chalmers J, Newton RW. How have patients reacted to the results of the Diabetes Control and Complications Trial? Diabetes Care 1996;19: 876-879. 
3. Howey DC, Bowsher RR, Brunelle RL, Woodworth JR. [Lys (B28), Pro (B29)] Human insulin: a rapidly absorbed analogue of human insulin. Diabetes 1994;43: 396-402. 
4. Anderson JH, Brunelle RL, Koivsto VA, Pfutzner A, Trautmann ME, Vignati L, Di Marchi R, the Multicenter Insulin Lispro Study Group. Reduction of postprandial hyperglycaemia and frequency of hypoglycaemia in IDDM patients on insulin-analog treatment. Diabetes 1997;46:265-270. 
5. Tuominen JA, Karonen S-L, Melamies L, Bolli G, Koivisto VA. Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue. Diabetologia 1995;38:106-111.
6. Anderson JH, Brunelle RL, Koivisto VA, Trautmann ME, Vignati L, DiMarchi R, the Multicenter Lispro Study Group. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Clinical Therapeutics 1997;19:62-72. 
7. Anderson JH, Brunelle RL, Keohane P, Koivisto VA, Trautmann ME, Vignati L, DiMarchi R. Mealtime treatment with insulin analog improves postprandial hyperglycaemia and hypoglycaemia in patients with non-insulin dependent diabetes mellitus. Arch Int Med 1997;157:1249-1255. 
8.  Ebeling P, Jansson P-A, Smith U, Lalli C, Bolli GB, Koivisto VA. Strategies toward improved control during insulin lispro therapy in IDDM. Diabetes Care 1997;20: 1287-1289. 
9. Zinman B, Tildesley H, Chiasson J-L, Tsui E, Strack T. Insulin lispro in CSII. Results of a double blind-crossover study. Diabetes 1997;46:440-443. 
10. Kotsanos JG, Vignati L, Huster W, Andrejasich C, Boggs MB, Jacobsen AM, Marrero D, Mathias SD, Patrick D, Zalani S, Anderson J. Health-related quality of-life results from multinational clinical trials of insulin lispro. Diabetes Care 1997;20:948-958.