Insulin lispro: experience in a private practice setting

These disadvantages have led to the development of the insulin analogue insulin lispro (Box 1). With its more rapid action it should alleviate many of these concerns. Patients can eat immediately after injecting insulin lispro, which is more convenient, and postprandial hyperglycaemia is much reduced.⁵ Lispro is more predictably absorbed, which should give fewer day-to-day blood glucose fluctuations, and, in turn, should reduce the risk of unpredictable hypoglycaemia by day and night,⁶ giving greater patient confidence. Patients should be able to reduce or cease between-meal snacks without an increased risk of hypoglycaemia, and this could lead to weight loss. However, when compared with treatment with regular insulin, glycohaemoglobin values (expressed as %HbA_1c) have been reported to change very little in unselected patient groups treated with lispro.^5,7

In this study, the effectiveness of lispro was assessed in a group of patients selected because they were having difficulty achieving smooth, safe and satisfactory glycaemic control with conventional insulins. A change to lispro was not offered to patients whose diabetes was well controlled without significant hypoglycaemia (ie, in this group the change was not made primarily for reasons of personal convenience). The objective was to ascertain whether their glycaemic control could be improved (without increasing the risk of hypoglycaemia in these unstable patients), and whether their health and their tolerance of diabetes could be improved.

All patients injected insulin four times daily using a basal-bolus insulin regimen. Lispro was injected using a 1.5 mL injector pen (B-D Pen, Aza Research, Sydney). Most patients (81%) injected Protaphane at bedtime using a NovoPen 3 (Novo Nordisk, Sydney), the remainder using other long-acting insulins (eg, Monotard [Novo Nordisk], Ultratard [Novo Nordisk] or Humulin UL [Aza]). No patient injected a long-acting insulin before breakfast.

All patients were asked to monitor their blood glucose level seven times daily initially, using their previous blood glucose monitor, before and two hours after meals and at bedtime, and were invited to telephone each morning before breakfast to report levels until their blood glucose and insulin doses were stable. Patients were instructed to use a sliding scale to adjust their lispro doses if their blood sugar levels were unexpectedly greater than 10 mmol/L or less than 5 mmol/L (Box 3).

An attempt was made to encourage patients with HbA_1cvalues below 7% to strive for higher blood glucose levels and to try to avoid their blood glucose level falling below 4 mmol/L, in the hope of decreasing lack of awareness of hypoglycaemia.

All patients were asked to complete a questionnaire (Box 4). All responses are entirely subjective, and no statistical analysis of these was undertaken.

Changes in HbA_1c values and body weight were recorded, usually after 4-6 months. For purposes of classification, a variation in HbA_1c between 2 0.2% and + 0.2% was regarded as no change, a rise or fall of 0.3%-0.9% as a minor increase/decrease, and a rise or fall of 1.0% or more as a major change. Similarly, a change in weight of 2 0.2 kg to + 0.2 kg was regarded as no change, a rise/fall of 0.3-1.9 kg as a minor increase/decrease, and a rise/fall of 2 kg or more as a major change.

Changes in insulin doses and HbA_1c are given as means and 95% confidence intervals (CIs) (Microsoft Excel). Correlations were determined by analysis of variance (ANOVA). Student's two-tailed t test was used to calculate the P values.

Insulin doses: Nearly all patients needed to adjust their insulin doses, but there was wide individual variation. More patients needed to reduce than increase the daily dose of lispro (52 v. 39 patients), while more increased their bedtime insulin than reduced it (62 v. 19 patients). However, the mean dose adjustments were small: the total daily dose of insulin rose by 1.3 units (95% CI, 0.11, 2.49), the dose of lispro was reduced by 0.4 units (95% CI, 2 0.76, 1.56), and the bedtime insulin dose rose by 1.8 units (95% CI, 0.88, 2.72).

Blood glucose fluctuation: Sixty-nine of 125 patients (55%) reported that their blood glucose level fluctuated less on lispro, 38 (30%) that there was no difference and 18 (14%) that their blood glucose levels fluctuated more. Fifty-one (41%) reported that their overall blood glucose levels were lower, 58 (46%) that there was no change, and 16 (13%) that their overall blood glucose levels were higher on lispro.

Glycohaemoglobin (%HbA_1c): In general, the changes in HbA_1c values agreed with the patients' perceptions of their overall blood glucose control. Sixty-five patients (52%) had a fall in HbA_1c of 0.3% or more, with 22 (18%) achieving an HbA_1c value at least 1.0% lower with lispro. In 22 patients (18%) the HbA_1c value rose by 0.3% or more, and in six patients (5%) it rose by 1.0% or more. From Box 5 it can be seen that the HbA_1c value did not change significantly in patients whose initial level was less than 8%, but there was a highly significant reduction in those with initially higher levels, and in the group as a whole. The greatest improvement was seen in patients with initial HbA_1c values of 8%-9%, of whom 51% (23/45) achieved HbA_1c values less than 8% (Box 6).

The group of patients whose HbA_1c value fell took slightly more insulin (3.35 units/day; 95% CI, 1.81, 5.16), while those whose HbA_1c value rose took slightly less (2 1.55 units/day; 95% CI, 2 4.17, 1.07). There was no correlation between individual changes in HbA_1c and the total daily insulin dose (r = 0.152, P = 0.08), but an increased bedtime insulin dose was weakly correlated with a lower HbA_1c value (r = 0.238, P < 0.02).

Hypoglycaemia: The frequency of both daytime and nocturnal hypoglycaemia was reduced after the change to lispro, as shown in Box 7. Seventy-eight patients (62%) noted fewer daytime episodes, with 53 patients (42%) reporting that they had experienced much less hypoglycaemia or none at all. The frequency of nocturnal hypoglycaemia was even more dramatically reduced, with 103 patients (82%) noting fewer episodes. Forty-one patients (33% of the total) became completely free of nocturnal hypoglycaemia.

Despite the reduction in episodes of hypoglycaemia, there was little change in hypoglycaemia awareness, 31 patients reporting that hypoglycaemia was harder to recognise, while 24 reported easier recognition. Only one patient complained of new hypoglycaemia unawareness. There was no apparent association between reduced awareness of hypoglycaemia and the HbA_1c value achieved with lispro, nor with major reductions in HbA_1c values.

Thirty-nine patients (31%) experienced a fall in HbA_1c value (mean, 1.0%; range, 0.3%-3.2%) associated with less daytime hypoglycaemia, and 52 patients (42%) achieved a lower HbA_1c value (mean, 0.9%; range, 0.3%-3.2%) associated with a reduction in nocturnal hypoglycaemia.

Weight: On changing to lispro, five patients were underweight, with body mass index (BMI) less than 20 kg/m², 69 were normal (20-25 kg/m²), and 51 were by definition overweight (BMI >25 kg/m²).

There was no systematic change in body weight: 55 patients lost weight, with 19 losing more than 2 kg, while 45 patients gained weight, of whom 25 gained more than 2 kg. There was no relationship between BMI at the commencement of the study and subsequent weight change, nor between weight change and changes in HbA_1c values.

Two-thirds of patients reduced their between-meal snacks, but only 18 (14%) were able to omit their mid-morning snack, while 33 (26%) and 26 (21%) were able to omit afternoon tea and bedtime supper altogether.

Wellbeing and satisfaction: If the 12 patients who withdrew from the study are included (making a total of 137 patients), 80 patients (58%) reported feeling physically better when taking lispro, and 48 (35%) said they were much better. Ninety-eight patients (72%) reported greater satisfaction with the new insulin regimen, of whom 64 (47%) said they were much more satisfied. Of the 125 patients who completed the study, 10 (8%) reported that they were less satisfied with treatment, with three patients being much less satisfied -- and to these must be added the 12 patients who withdrew because of dissatisfaction with lispro, making a total of 16% (22/137).

Patients were selected because of difficulties with their glycaemic control or hypoglycaemia rather than for personal convenience, and this may partly explain the different results from those in earlier studies of lispro,^5,7 in which no significant change in HbA_1c was noted in cohorts of unselected patients.

The aim was to provide an insulin regimen which would minimise the risks of both hypoglycaemia and long term complications. Results from the Diabetes Control and Complications Trial (DCCT) suggest that there is a curvilinear relationship between high HbA_1c values and an increased risk of microvascular complications, and that a similar curvilinear relationship exists between lower HbA_1c values and an increased risk of severe hypoglycaemia and hypoglycaemia unawareness.⁸ In practice, achieving HbA_1c values between 7% and 8% seems to offer reasonable protection against both problems.

During routine therapy with regular insulin the use of a sliding scale to correct unexpected high or low blood glucose levels is not logical, as this insulin works too slowly to achieve the desired result; however, with lispro, patients can add or subtract small doses, which helps in returning aberrant glucose levels to the desirable range more quickly. Most patients learn to use this method easily.

More than half the group experienced a fall in HbA_1c, which in 20% of patients was 1% or more. The greatest improvement occurred in patients whose initial HbA_1c value was only moderately elevated (HbA_1c, 8%-9%), and, of these subjects, more than 50% were able to achieve a value which, according to results from the DCCT,⁸ should offer better protection against microvascular complications. However, although patients with initially poor glycaemic control (HbA_1c, >9%) often achieved HbA_1c values less than 9%, only 4 of 24 (17%) achieved values below 8%; the remainder must be regarded as being still at increased risk of complications.

Most patients in whom HbA_1c values were initially less than 7% proved resistant to attempts to raise their blood glucose level, with only a third achieving HbA_1c values of 7% or higher (Box 6). According to the DCCT, the risk of hypoglycaemia unawareness in this group is considerable,⁸ and it is pleasing to note that 10 of these 15 patients (Box 6) experienced less daytime hypoglycaemia and 13 had less nocturnal hypoglycaemia, with no significant change in hypoglycaemia awareness. Patients, their relatives and their physicians all welcome any reduction in risk of hypoglycaemia, and many will deliberately try to avoid hypoglycaemia by reducing insulin doses, even though this leads to poor overall glycaemic control and increases the risk of microvascular complications. It is particularly gratifying that 31% of the patients had less daytime hypoglycaemia and 42% had less nocturnal hypoglycaemia associated with a fall in HbA_1c value, indicating greater safety together with better glycaemic control.

A lower frequency of hypoglycaemia should be associated with improved hypoglycaemia awareness,⁹ but this did not eventuate. On the other hand, there was little evidence of any progression of hypoglycaemia unawareness over the short duration of the study.

There was no correlation between individual changes in HbA_1c and changes in either the daily dose of lispro or the total daily insulin requirement. Dose adjustments were small, but an inverse correlation was found with the bedtime insulin dose; this was sufficiently weak to indicate that other factors are likely to have contributed to this finding.¹⁰

Insulin lispro does not suit every patient with type 1 diabetes, but with careful education in its use many experience significant benefits, and achieve greater confidence and satisfaction. The advent of new long-acting and short-acting insulin analogues in the near future is awaited with interest; they will need careful clinical evaluation by both patients and their treating physicians.

Conflict of interest:

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Reprints will not be available from the author.
Correspondence: Dr A E Stocks, Brisbane Clinic, 79 Wickham Terrace, Brisbane, QLD 4000.

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