Owens p-66 8/5/07 4:19 pm Page 1 Insulin glulisine the potential for improved glycaemic control DAVID R OWENS Abstract Tight glycaemic control is essential to reduce the risk of developing the micro- and macrovascular complications of diabetes. Plasma levels of glycosylated haemoglobin (HbA 1C ) are a marker for long-term glycaemia; controlling these levels within tight limits forms the cornerstone of long-term diabetes management. As a result of evidence from key clinical trials in type 1 and type 2 diabetes, HbA 1C targets ranging from < 6.5 to < 7.5% have been set by various authorities. To achieve these targets, insulin regimens need to reflect normal physiological insulin release. Several rapid- and long-acting insulin analogues have been developed to mimic aspects of insulin secretion. Insulin glulisine is a genetically engineered insulin which has a rapid onset and short lived action, allowing it to closely mimic prandial release of insulin. In addition to the structural change in the insulin molecule, the absence of excess zinc and the addition of polysorbate 20 as a surfactant facilitates its disassociation in the subcutaneous tissue and inhibits its aggregation when used in subcutaneous insulin delivery systems due to improved physical stability. Br J Diabetes Vasc Dis 2007;7:-66 Key words: insulin glulisine, pharmacokinetics, pharmacodynamics, type 1 diabetes, type 2 diabetes. Correspondence to: Professor David R Owens Diabetes Research Unit, 1st Floor Academic Centre, Llandough Hospital Penlan Road, Penarth, CF64 2XX, UK. Tel: +44 (0)2920 716928; Fax: +44 (0)2920 350147 E-mail: owensdr@cardiff.ac.uk David R Owens Introduction Evidence that tight glycaemic control reduces the risk of microand macrovascular complications of diabetes continues to accrue. It is well established that tight glycaemic control significantly lowers the risk of microvascular complications in both type 1 and type 2 diabetes. 1,2 The DCCT/EDIC study demonstrates a significant association between tight glycaemic control and a reduction in the risk of cardiovascular events in type 1 diabetes. 3 Over the 10 years of the complementary trial in type 2 diabetes, the UKPDS, HbA 1C was 7.0% in a group intensively treated with sulphonylureas or insulin versus 7.9% in a conventionally nonpharmacological treated group. This improvement in glycaemic control was associated with a 16% reduction in the risk of MI, (p=0.052). 1 UKPDS has also shown that individuals who suffered a fatal MI had a higher HbA 1C than those who suffered non-fatal MI, with a 17% reduction in the odds of suffering MI per 1% reduction in HbA 1C (p=0.014). 4 Several UK initiatives have been published in an attempt to incorporate these important research findings into everyday clinical practice, including the NSF for Diabetes, the NICE guidelines and the GMS contract policy initiative. 5-7 These strategies are important as the number of patients who do not achieve adequate control of glycaemia and have associated vascular risk factors remains unacceptably high. This situation has led to an increased focus on the development of effective insulin regimens to optimise control of glycaemia and to reduce vascular risk. 8,9 The quest for long-term maintenance of optimal glycaemia has also led to the increasing recognition of the need for timely introduction of insulin therapy in those with type 2 diabetes. 9 Since 1996, optimal glycaemic control through the use of more effective insulin regimens has been brought a step closer with the introduction of long-acting insulin analogues, such as insulin glargine (in 2000) and insulin detemir (in 2004), and rapid acting insulin analogues, such as insulin lispro (in 1996), aspart (in 1999) and, most recently, insulin glulisine (at the end of 2004). These rapid-acting insulin analogues were genetically engineered to more closely mimic physiological insulin delivery in response to a nutrient challenge. THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Owens p-66 8/5/07 4:19 pm Page 2 Abbreviations BMI body mass index CC creatinine clearance CSII continuous subcutaneous insulin infusion GMS General Medical Service HbA 1C haemoglobin A 1C NICE National Institute for Clinical Excellence NPH Neutral Protamine Hagedorn NSF National Service Framework MI myocardial infarction RHI regular human insulin SMBG self monitoring of blood glucose Limitations of regular human insulin Glycaemic control Fasting and mealtime (prandial) glycaemia contribute to overall glycaemic control, and these must be addressed to achieve effective diabetes management. 15 Postprandial glucose is a major contributor to total glycaemic control where HbA 1C levels are below approximately 7%, whilst fasting blood glucose is the major contributor where HbA 1C is higher. 15 The DECODE study reported increased cardiovascular risk associated with hyperglycaemia after a glucose challenge. 16 The evidence for the molecular mechanisms by which this postprandial hyperglycaemia accelerates the atherosclerotic process is accumulating. 17 Until the development of the insulin analogues in the mid 1990s, the most effective method of achieving good glycaemic control was the use of a combination of short-acting formulations of RHI and longer-acting isophane or lente insulin preparations. However, RHI is not ideal for the control of prandial glycaemia; because of its conjugation to zinc which stabilises the hexameter and retards its dissociation, thereby slowing its absorption from the subcutaneous tissue. It has an onset activity of about 30 minutes following subcutaneous injection, with the concentration in the blood reaching a plateau at 2 3 hours followed by a slow fall to baseline over the subsequent 6 10 hours. 18 Acronyms DCCT/EDIC DECODE HPS UKPDS Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe study Heart Protection Study United Kingdom Prospective Diabetes Study This article highlights certain molecular and clinical attributes that mark insulin analogues as potentially important advances in the evolution of effective prandial insulin therapy and focuses on insulin glulisine. Insulin glulisine differs from human insulin by the replacement in the B-chain of the amino acid asparagine with lysine at position three and lysine with glutamic acid at position 29. These changes reduce the tendency for the insulin glulisine molecule to form dimers by inducing slight steric and electrostatic repulsion between two insulin monomers, which also incresases the rate of dissociation in the subcutaneous tissue and consequently its absorption leading to a more rapid onset of action compared to RHI 10-12 Insulin glulisine has been shown in obese normal subjects to have advantages over insulin lispro and RHI in terms of absorption at different levels of BMI and subcutaneous fat thickness. 13 This trend has also been seen in a small study involving subjects with type 2 diabetes, but the difference only achieved a small impact on the postprandial glucose profiles in these subjects. 14 Adverse events and compliance Intensive insulin therapy with conventional insulin regimens is associated with weight gain and risk of hypoglycaemia. The DCCT showed that intensifying conventional insulin treatment reduced the risk of diabetic complications. 2 However, there were 62 hypoglycaemic episodes per 100 patient-years in the intensive treatment arm of the DCCT, compared with 19 such episodes per 100 patient-years in the conventional treatment group. 2 Patients in the intensive treatment arm also gained 4.6 kg more in weight than those in the comparator group. Administration of RHI up to half an hour before meals may also be a barrier to compliance. Patients frequently ignore this recommendation in favour of injecting at a more convenient time, 19 which leads to suboptimal glycaemic control and an increased risk of interprandial and/or nocturnal hypoglycaemia. 20 Improving the pharmacodynamics of insulin through genetic engineering An ideal insulin regimen would achieve tight glycaemic control and avoid hypoglycaemia whilst allowing mealtime flexibility and convenience of administration. The advent of recombinant DNA technology has facilitated the availability and production of rapid-acting (figure 1) and longer-acting and peakless basal insulin analogues. 18,21 Such molecular modifications are taking us a step closer to reaching an ideal regimen. Further modification in the zinc content and additives used in the pharmaceutical preparations can further influence the pharmacokinetics, pharmacodynamics and stability of the insulin analogues. With rapid-acting insulin analogues, changes in the amino acid structure promote charge repulsion, which reduces the tendency of the protein to remain aggregated in the hexameric and dimeric state thus increasing the rate of absorption from the subcutis. 10 (figure 1) Pharmacokinetics and pharmacodynamics of insulin glulisine versus RHI In a phase I, cross-over study in 16 healthy individuals without diabetes, insulin glulisine efficacy was equivalent to RHI. Using the euglycaemic clamp method 23 at steady-state (90 120 minutes after the start of 0.08 mu kg -1 /min -1 insulin infusion), VOLUME 7 ISSUE 2. MARCH/APRIL 2007 61
Owens p-66 8/5/07 4:19 pm Page 3 Figure 1. Amino acid structure of the three rapid-acting insulin analogues A Chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn Insulin lispro 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 B Chain Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Lys Pro Thr 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 A Chain B Chain A Chain B Chain Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 insulin glulisine and RHI achieved similar glucose utilisation (GIR-AUC SS 214 mg/kg -1 and 209 mg/kg -1, respectively), glucose infusion rates (GIR SS 1050 mg/kg -1 and 995 mg/kg -1, respectively) and total glucose disposal rates (GIR-AUC 0 clamp end 1050 mg/kg -1 and 995 mg/kg -1, respectively). 23 The rate of absorption of insulin glulisine is equivalent to the rapid-acting insulin analogue, insulin lispro, and almost twice as fast as RHI (T max 56, 50 and 99 minutes, respectively). 24 Additionally, both rapid-acting analogues had a lower mean residence time and duration of action than RHI. Insulin glulisine can be used in CSII systems owing to the use of polysorbate 20 as an excipient. This improves the stability of insulin exposed to thermal and mechanical stress, which otherwise would lead to catheter occlusion due to autocatalytic fibrie formulation with insulin precipitation. 25 A 12-week, randomised, open-label study involving 59 patients with type 1 diabetes, found no significant differences in efficacy or safety Insulin aspart Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Asp Lys Thr 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Insulin glulisine Phe Val Lys Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Glu Thr 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Insulin lispro is so named because of the substitution of amino acids lysine (lys) and proline (pro) at positions B28 and B29 in place of proline and lysine, respectively, in normal human insulin. Insulin aspart, meanwhile, has aspartate at position B28 instead of proline. In the case of glulisine, the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. 22 These modifications result in a faster rate of absorption and onset of action and with a shorter duration of action compared with RHI between insulin glulisine and insulin aspart when used in CSII systems. The rate of catheter occlusions in the insulin glulisine and insulin aspart groups was 0.08+0.2 and 0.15+0.3 occlusions/month, respectively (p=0.06). One patient in the insulin aspart group suffered unexplained hyperglycaemia associated with catheter occlusion while unexplained hyperglycaemia in the presence or absence of pump occlusions occurred in 6 patients (20.7%) in the insulin glulisine group compared with 12 patients (40.0%) in the insulin aspart group. It should be noted, however, that catheter occlusions are not a commonlyreported problem and caution should be taken before altering clinical practice based on the evidence from a single study. Infusion site reactions occurred in three patients in the insulin glulisine group and in four patients receiving insulin aspart. End point HbA 1C levels were similar in the insulin glulisine and insulin aspart treated groups (6.98% and 7.18%, respectively). 26 62 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Owens p-66 8/5/07 4:19 pm Page 4 Further phase I studies have shown that the absorption, pharmacokinetics and glucodynamics of insulin glulisine are largely unaffected by the site of injection 27 and its pharmacokinetics are consistent across a range of populations. 28 It is known that obesity adversely affects the absorption of RHI and the consistency of the pharmacokinetic profile of rapid-acting insulin analogues in obese versus non-obese individuals will potentially have particular importance for the control of postprandial hyperglycaemia in patients with type 2 diabetes. In a randomised study of 18 obese individuals without diabetes (mean BMI 34.7 kg/m 2 ), insulin glulisine and insulin lispro had a more marked rapid time action profile compared to RHI. Compared to RHI and insulin lispro, the pharmacokinetics and pharmacodynamics of insulin glulisine were less influenced by subcutaneous adiposity and not significantly related to BMI. 13 The relationship between BMI and insulin aspart was investigated in a separate study of obese individuals with type 1 diabetes. 29 Increasing obesity was associated with a decreased apparent clearance rate per kg body weight, increased half-life and increased insulin area under the curve, but these results were not considered to be clinically significant by the authors as the changes observed were less than the individual variations for these parameters. The pharmacokinetics of insulin glulisine and RHI were also compared in a single-dose study involving ten children (aged 5 11 years) and ten adolescents (aged 12 17 years) with type 1 diabetes. 30 In this randomised, cross-over study, mean residence time for insulin glulisine was distinctly shorter at 88 minutes compared with 137 minutes for RHI (p<0.05), and the insulin C max and AUC 0 2h were 76% and 75% higher for insulin glulisine compared with RHI (p<0.05 for both observations). Therefore, the pharmacokinetic differences between insulin glulisine and RHI observed in children and adolescents mirrored those observed in adults. A single-dose study examined the pharmacokinetics of insulin glulisine in non-diabetic individuals (mean age 56 years; mean BMI 26 kg/m2) with normal renal function (CC > 80 ml/min, n=8), moderately impaired renal function (CC 30 50 ml/min, n=8) or severely impaired renal function (CC < 30 ml/min, n=8). No apparent differences in the insulin glulisine concentration time profiles were observed for the three subgroups and there was no relationship between the estimated creatinine clearance and the rate of onset or duration of action. The authors concluded that dose adjustments for renal insufficiency, other than those required to compensate for any co-existing level of insulin resistance, would be unnecessary. 31 Any requirement to reduce the dose in individual subjects with end-stage renal disease will need to be based on clinical judgement. Table 1. Mean blood glucose measurements 33 patients with type 1 diabetes on basal (insulin glargine) bolus (insulin glulisine or RHI) regimens Pre-meal RHI Pre-meal Post-meal (30 45 min) (0 15 min) (0 15 min) insuline insulin glulisine glulisine 2-hour post-breakfast glucose levels (mmol/l) 7.83+0.17 9.10+0.17 8.57+0.17* 2-hour post-dinner glucose levels (mmol/l) 8.12+0.19 9.23+0.19 8.77+0.19** Key: *p=0.0017, **p=0.0137, p=0.0001 vs. pre-meal RHI Clinical efficacy of insulin glulisine versus RHI Insulin glulisine versus RHI in type 1 diabetes In addition to the differences in the pen injected devices between different insulins, which in itself may be an important aspect of patient acceptability of any treatment, the requirement to inject RHI 30 minutes before a meal places constraints on patients and limits mealtime flexibility. Rapid-acting insulin analogues provide a more convenient option for prandial glucose control, as demonstrated in studies of insulin glulisine versus RHI in patients with type 1 diabetes. 32 In a single-dose, four-arm, cross-over study, insulin glulisine was administered either immediately before or 15 minutes after a standard meal whereas RHI was administered either immediately or 30 minutes before the same standard meal. The study compared the relative abilities of these regimens to control postprandial blood glucose levels in 20 patients with type 1 diabetes. 32 The study results showed that insulin glulisine given pre-meal (0 15 minutes) provided more effective prandial glucose control than RHI, when administered 30 minutes before the meal (figure 2). A further trial of 8 patients with type 1 diabetes was undertaken, 33 in which all patients received once-daily insulin glargine and were randomised to one of three treatment groups: insulin glulisine 0 15 minutes before meals, insulin glulisine 0 15 minutes after meals or RHI 30 45 minutes before meals. 33 Reductions in HbA 1c were similar for the postmeal insulin glulisine and pre-meal RHI groups (-0.11 and -0.13%, respectively), but were significantly greater in the premeal insulin glulisine group (-0.26%) vs. RHI (p=0.02) and vs. post-meal insulin gluisine (p=0.0006). Giving insulin gluisine post-meal achieved equivalent overall glycaemic control to RHI given before the meal. The pre-meal administration of insulin glulisine was more effective than post-meal insulin glulisine and RHI in reducing postprandial glycaemia (table 1). Post-meal insulin glulisine was associated with a mean 0.3 kg weight reduction compared to a mean 0.3 kg weight gain for pre-meal RHI (p=0.03). Results of the safety assessments, including the incidence of hypoglycaemia, were similar among the three groups. Importantly, these results support the hypothesis that rapidacting insulin analogues provide more mealtime flexibility. A VOLUME 7 ISSUE 2. MARCH/APRIL 2007 63
Owens p-66 8/5/07 4:19 pm Page 5 Figure 2. Insulin glulisine (GLU given 0 2 minutes prior to the standard meal provides more effective glucose disposal than regular human insulin (RHI) 0 2 minutes prior to the test meal. Glulisine immediately pre-meal was equivalent to RHI given 30 minutes before the standard meal. Giving insulin glulisine 15 minutes after the meal was equally effective to pre-meal RHI GLU pre-meal vs. RHI 30 minutes pre-meal GLU pre-meal vs. RHI pre-meal GLU post-meal vs. RHI pre-meal 220 220 220 Glucose (mg/dl) Key: 200 180 1 140 120 100 80 GLU (pre) RHI (30 minutes) -1 0 1 2 3 4 5 6 7 Time (hours) sub-analysis of this study also highlights the potential of rapidacting analogues to reduce insulin dose in patients with type 1 diabetes, when titrated to blood glucose targets and avoiding hypoglycaemia. 34 While 32.7% of those receiving pre-meal RHI were able to reduce their total daily insulin dose, a significantly greater proportion of those receiving insulin glulisine pre- and post-meal reduced their insulin dose by 46.1% and 46.6% respectively (p=0.0014 vs. RHI and p=0.0008 vs. RHI, respectively). The sub-analysis further illustrated the beneficial effects of insulin glulisine on weight gain over the 12-week study period: 37.6% in the RHI group, 32.2% in the pre-meal insulin glulisine group and 26.0% in the post-meal insulin glulisine group gained > 1 kg in body weight. The difference for post-meal insulin glulisine versus RHI reached statistical significance (p=0.0035). Glucose (mg/dl) 200 180 1 140 120 100 80 GLU (pre) RHI (pre) -1 0 1 2 3 4 5 6 7 Time (hours) indicates meal administration; GLU = glulisine; RHI = regular human insulin Glucose (mg/dl) 200 180 1 140 120 100 80 GLU (post) RHI (pre) -1 0 1 2 3 4 5 6 7 Time (hours) Insulin glulisine versus RHI in type 2 diabetes A similar study was undertaken in persons with type 2 diabetes to examine the safety and efficacy of insulin glulisine versus RHI. In this study, a basal bolus regimen was used in a multicentre, open-label, 26-week trial. 35 A total of 867 patients who were relatively well controlled (mean HbA 1C of 7.6%) with insulin alone or insulin plus oral antidiabetic therapy were randomised to receive treatment with either insulin glulisine plus NPH insulin or RHI plus NPH insulin. A greater reduction in HbA 1C from baseline was observed in the insulin glulisine group compared with the RHI treatment group (-0.46% vs. -0.30%, p=0.0029). Subjects in this study conducted SMBG, recording seven data points at set times during the day. In contrast to baseline values, which were comparable for the two groups, the SMBG values were lower in persons receiving insulin glulisine than in those receiving RHI. The differences were statistically significantly different for blood glucose values reached two hours after breakfast and two hours after dinner (p<0.05). 35 As with studies in type 1 diabetes, the safety assessments showed no significant differences in the rates of adverse events between insulin glulisine and RHI, including injection site reactions (3.2% vs. 2.3% for insulin glulisine and RHI, respectively). 30 These results in patients with type 2 diabetes show the potential of preprandial insulin glulisine to provide equivalent or better overall glycaemic control to preprandial RHI when used to improve prandial glucose control, without causing additional weight gain or increasing the risk of hypoglycaemia. Insulin glulisine a step towards optimal glycaemic control Reducing the risk of vascular complications remains the primary focus of diabetes management. While the contribution of hyperglycaemia to microvascular complications has long been established, its role in macrovascular complications is becoming increasingly apparent. The development of rapid-acting insulin analogues provides a significant step towards achieving optimal glycaemic control by providing improved prandial glucose control. Whilst the safety of insulin glulisine has been demonstrated in children and adolescents, 30 future longer-term studies of this 64 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Owens p-66 8/5/07 4:19 pm Page 6 Key messages Tight glycaemic control can reduce vascular complications of diabetes. Optimal glycaemia requires effective treatment regimens which mirror physiological insulin release Insulin glulisine is a genetically engineered insulin with a rapid onset of action which closely mimics prandial insulin release. Its short duration of action reduces the risk of interprandial hypoglycaemia In type 2 diabetes insulin glulisine has been shown to improve HbA 1C levels compared with regular human insulin The pharmacokinetics and pharmacodynamics of insulin glulisine in contrast to regular human insulin are less influenced by BMI in non-diabetic patients. If these reflect the situation in obese people with diabetes, then this may indicate that effectiveness would be maintained in such individuals of insulin gluisine rapid-acting insulin analogue are needed to include studies in pregnant women, to determine the safety profile for both the mother and the unborn child. Further studies of the rapid-acting insulin analogues will also allow the evaluation of better control of postprandial hyperglycaemia on the atherosclerotic process. Insulin glulisine provides benefits including significantly more effective control of HbA 1C levels compared to RHI in a basal bolus regimen with NPH in persons with type 2 diabetes. Its rapid onset of action is maintained over a wide range of BMIs. The flexability to administer insulin glulisine pre- and post-meal provides added convienience. Further potential potential benefits includes limiting weight gain compareed to RHI for equivalent glycaemic control in persons with type 1 diabetes. Conclusion Insulin glulisine will provide healthcare professionals with an additional therapeutic option that may increase their ability to improve prandial glucose control and better meet national standards of diabetes care. This should lead to a reduction in the massive burden of vascular disease that is currently associated with diabetes. References 1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. 2. The Diabetes Control and Complications (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. 3. The DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. 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