- Email: [email protected]
Getting closer to physiologic insulin secretion
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Clinical Therapeutics/Volume 29, Supplement D, 2007
Getting Closer to Physiologic Insulin Secretion Tim Heise, MD Profil Institute for Metabolic Research, Neuss, Germany
ABSTRACT
INTRODUCTION
Background: The goal of insulin replacement therapy in diabetes mellitus (DM) is to recreate a normal physiologic insulin supply throughout the day. Objective: This article reviewed the use of rapidacting insulin analogues in recreating physiologic postprandial insulin responses. Methods: This review article was based on a presentation at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues” that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. Results: In the context of mealtime insulin supply, recreating physiologic postprandial insulin responses requires rapid availability of insulin within a short time of eating and a duration of action that does not extend into the late postprandial period. Conventional human insulin is not ideally suited to SC injection, with its slow onset of action and dose-dependent duration of action. The rapid-acting insulin analogues have been designed to address these deficiencies, with more rapid onset of action, higher maximal effects, and consequently better postprandial glycemic control. These properties have been reported in patients with type 1 and type 2 DM, as well as in nondiabetic individuals in euglycemic clamp studies. Rapid-acting insulin analogues are also of particular interest in people with diabetic nephropathy, women with gestational DM, and elderly patients with DM. Conclusions: Compared with soluble human (regular) insulin, rapid-acting insulin analogues have a more rapid onset of action and a shorter duration of action. Their potential in special patient groups is now being established in clinical research and in everyday practice. (Clin Ther. 2007;29[Suppl D]: S161–S165) Copyright © 2007 Excerpta Medica, Inc. Key words: insulin analogues, euglycemic clamp, type 1 diabetes mellitus, type 2 diabetes mellitus, insulin aspart.
A swift response is essential when seeking to match physiologic insulin supply. The nondiabetic individual responds to a glucose load with a prompt first-phase insulin response that is blunted or absent in individuals with type 2 diabetes mellitus (DM).1 The effect on glycemic control of replacing early prandial insulin has been described in detail by Bruce et al.2 Insulin was administered intravenously to 8 patients with type 2 DM (mean [SD] age, 62.0 [6.8] years; 7 males, 1 female); 9 nondiabetic individuals (mean [SD] age, 59.2 [8.3] years; 6 males, 3 females) were used as controls. When the total dose of insulin (1.8 U) was delivered within 30 minutes of a mixed meal (breakfast cereal, 30 g; milk, 150 mL; orange juice, 150 mL; 2 slices of toast, 30 g each; butter, 10 g; 2 cups of decaffeinated coffee), the peak glucose increment was reduced to a level similar to the nondiabetic controls; however, if the same insulin dose was delivered between 30 and 60 minutes after the meal, or administered evenly over 180 minutes, glycemic response to the meal was unimproved, showing the importance of insulin availability during the early postprandial period. The purpose of this article was to review the use of rapid-acting insulin analogues in meeting the goal of recreating physiologic postprandial insulin responses.
2007
METHODS This review was based on a presentation at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues” that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa.
Accepted for publication November 7, 2007. doi:10.1016/j.clinthera.2007.12.012 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc.
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LIMITATIONS OF CONVENTIONAL EXOGENOUS INSULIN THERAPY Exogenous insulin is not delivered intravenously in everyday life, and conventional SC insulin cannot replicate its speed of action. Heinemann et al3 compared the time–action profiles of IV and SC regular insulin in a euglycemic clamp study in 12 healthy male volunteers (mean [SD] age, 25 [2] years). Onset of action was much slower with subcutaneously injected insulin: mean half-maximal effect was reached after 54 minutes compared with 7 minutes for IV insulin, and mean maximal effect was reached after 147 minutes and 14 minutes with SC and IV insulin, respectively. The limitation of subcutaneously administered conventional insulin becomes even more apparent with higher doses. Nosek et al,4 in a 6-way crossover euglycemic clamp study in 14 healthy volunteers (mean [SD] age, 28 [4] years; 10 males, 4 females), examined the dose dependency of the pharmacodynamics of 6, 12, and 24 U of conventional soluble human insulin. They reported a significant increase in the duration of action with higher doses, indicated by a significant increase in total glucose infusion requirement from 6 to 12 hours (P < 0.05). As a consequence of its onset of action and varying duration of action, conventional insulin may be incapable of adequately controlling postprandial glucose excursions; this problem means that soluble human insulin has to be injected several minutes before a meal. However, patients often fail to use an adequate injection– meal interval,5 which further negatively impacts postprandial glucose control. This was illustrated in a study by Brunner et al6 of 20 patients (mean [SD] age, 36.4 [11.2] years; 12 males, 8 females) with type 1 DM. Peak postprandial glucose concentrations were 13.3 mmol/L with human insulin, injected 15 minutes before a test meal; these concentrations worsened to 14.1 mmol/L when the insulin was injected at the time of the meal.
RAPID-ACTING INSULIN ANALOGUES The limitations of conventional insulin, and the need for insulins with improved pharmacodynamics, have been recognized for some years,7 and several modified insulins have been produced. Three rapid-acting insulin analogues are available: insulin lispro (Lys[B28], Pro[B29] human insulin), insulin aspart (Asp[B28] human insulin), and insulin glulisine (Lys[B3], Glu[B29] human insulin). These molecules were deS162
signed to reduce both the time to onset of metabolic effect and the duration of that effect by weakening the associative interactions between insulin monomers, thus enabling more rapid dissociation of insulin hexamers, compared with human insulin, after SC injection.8 Compared with soluble human (regular) insulin, rapid-acting insulin analogues have a more rapid onset of action and a shorter duration of action. In the study by Nosek et al,4 no significant increase in late metabolic activity (beyond 6 hours postdosing) was observed when insulin aspart doses of 6, 12, and 24 U were compared. All doses of insulin aspart showed higher maximal effects, and more rapid onset of action, than corresponding doses of soluble human insulin, with significantly lower (P < 0.05) total glucose infusion from 6 to 12 hours postdose (Figure). Similar results have also been reported for insulin lispro.9 Therefore, rapid-acting insulin analogues, such as insulin aspart, are able to control postprandial glucose excursions to a greater extent than soluble human insulin, even when the latter is dosed several minutes preprandially, as found in the study by Brunner et al.6 In this study of patients with type 1 DM, maximum plasma glucose levels after a test meal were significantly lower with insulin aspart dosed at the time of the meal (11.2 mmol/L) than with human insulin dosed at the time of the meal or 15 minutes before the meal (13.3 and 14.1 mmol/L, respectively; both, P < 0.05 vs insulin aspart). This advantage of the modern rapid-acting insulin analogue is especially evident when a high-carbohydrate meal is consumed. Heinemann et al10 investigated postprandial glycemia in 10 type 1 DM patients (mean [SD] age, 29 [3] years) after they had consumed a “fast-food” meal of pizza, cola, and carbohydraterich dessert. Comparison of insulin lispro with soluble human insulin showed a 22% reduction in total blood glucose excursion (1.76 vs 2.26 mmol/L · 240 min; P < 0.01) and lower maximal glucose concentrations (9.9 vs 11.9 mmol/L; P < 0.05).
SPECIAL PATIENT GROUPS The improved pharmacodynamics of rapid-acting insulin analogues are of value in DM management in general because they provide a better approximation to normal physiologic insulin release. In addition, there are a number of special patient groups that might benefit in particular from their use: these inVolume 29 Supplement D
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T. Heise
Insulin aspart Soluble human insulin
2100 1900
GIR AUC 6–12 h (mg/kg)
161_heise
†
†
1700 1500
*
*
*
1300 1100 900 0 6
12
24
Insulin Dose (U) Figure. Time–action characteristics (glucose infusion rates [GIR] 6–12 hours after dosing) of the rapid-acting insulin analogue insulin aspart and soluble human insulin, at doses of 6, 12, and 24 U, in healthy volunteers. Values are given as mean (SD). *P < 0.05 for insulin aspart versus soluble human insulin; †P < 0.05 for soluble human insulin versus 24 U of soluble human insulin. Data from Nosek et al.4
clude individuals with diabetic nephropathy, women with gestational DM, and elderly patients with DM.
Patients with Diabetic Nephropathy Diabetic nephropathy tends to prolong the duration of action of insulin, due to reduced renal insulin clearance; individuals with nephropathy may therefore be at increased risk of hypoglycemia and poorer metabolic control.11,12 Rave et al13 found that insulin lispro had a shorter duration of action than conventional soluble human insulin in patients with diabetic nephropathy. In this euglycemic clamp study of 12 patients (mean [SD] age, 41 [5] years; 6 males, 6 females) with type 1 DM and proteinuria >500 mg/24 h and/or serum creatinine >1.5 mg/dL, mean peak insulin levels were higher (359 vs 213 pmol/L; P < 0.05) and mean time to maximum insulin levels shorter (85 vs 118 minutes; P < 0.05) after injection of insulin lispro versus injection of soluble human insulin, respectively. Mean maximal metabolic effect (as measured by the glucose infusion rate) was higher with insulin lispro than with soluble human insulin (5.4 vs 3.4 mg/kg · min; P < 0.003) and was achieved earlier (102 vs 191 minutes; P < 0.003). Importantly, mean du2007
ration of action (assessed by time to late half-maximal metabolic effect) was also significantly shorter with insulin lispro than with soluble human insulin (244 vs 343 minutes; P < 0.003). The faster onset of action and shorter duration of action of rapid-acting insulin analogues could therefore achieve acceptable glucose control without an increased risk of hypoglycemia, especially in people with diabetic nephropathy.
Women with Gestational Diabetes Mellitus For women with gestational DM, it is important for them to reach acceptable—and even normal, if possible—levels of glucose control (including postprandial glucose concentrations comparable to those in healthy people) to reduce the risk of adverse maternal and fetal outcomes. Therefore, women with gestational DM may benefit from using rapid-acting insulin analogues to achieve better postprandial glucose control. Pettitt et al14 reported in 15 women with gestational DM that insulin aspart, given 5 minutes before the meal, significantly reduced postprandial glucose excursions (mean glucose AUC at 180 minutes, 7.1 [7.9] mg 䡠 h 䡠 dL–1; P = 0.018 vs no insulin), whereas soluble human insulin, injected 30 minutes preprandiS163
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Clinical Therapeutics ally, was unable to significantly reduce postprandial glucose excursions versus no exogenous insulin (mean glucose AUC at 180 minutes, 30.2 [6.1] mg 䡠 h 䡠 dL–1; P = 0.997). Based on C-peptide measurements, administration of insulin aspart reduced the demand for endogenous insulin after the meal. Because insulin aspart has been approved for use in pregnancy, this analogue might be an option to improve postprandial glucose excursions and thereby maternal and fetal outcomes in pregnancies affected by DM.15,16
CONCLUSIONS Modern rapid-acting insulin analogues were developed to more closely mimic physiologic postprandial insulin responses. Because of their faster onset of action and their shorter duration of action, these agents can effectively control postprandial glucose excursions significantly better than soluble human insulin. Their potential in special patient groups is now being established in clinical research and in everyday practice.
ACKNOWLEDGMENTS Elderly Patients with Diabetes Mellitus Rapid-acting insulin analogues are also of particular interest in patient groups with unpredictable eating habits, such as the elderly. Unlike conventional insulin, insulin aspart can be injected postprandially without loss of postprandial glucose control.6,17 In a study of 19 patients with type 1 DM (age range, 22–82 years), postprandial glucose excursions were not significantly different when insulin aspart was injected 0 to 5 minutes before the start of, or immediately after, a test meal (baseline-adjusted postprandial excursion, 4487 and 5751 mg/dL · min, respectively).17 Similar results have been obtained with insulin lispro.18 The use of insulin analogues in elderly patients has not been extensively studied; however, the pharmacodynamics of insulin aspart and soluble human insulin were compared by Krones et al19 in a euglycemic clamp study of 19 elderly subjects (mean age, 70 years) with type 2 DM. They determined that, in accordance with results found in other patient groups (eg, children and adolescents with type 1 DM,20 patients with type 1 DM and renal or hepatic impairment21), insulin aspart had a faster onset of action than soluble human insulin (glucose infusion 0–2 hours, 265 vs 112 mg/kg; P < 0.05) and a shorter duration of action (time to late half-maximal action, 348 vs 497 minutes, respectively). Although more clinical evidence is needed, the pharmacodynamic characteristics of insulin aspart in elderly patients which are similar to those in younger patients suggest that postprandial administration of this agent has the potential to be successful in the elderly population. This should allow titration of insulin according to the real—rather than the expected—carbohydrate intake, thereby minimizing the risk of postprandial hypoglycemia in patients with unpredictable eating habits. S164
The publication of this article was supported by Novo Nordisk A/S (Bagsværd, Denmark). The author has received research grants and honoraria for presentations and participation in advisory boards from several pharmaceutical companies, including the insulin-producing companies Novo Nordisk A/S, Eli Lilly and Company (Indianapolis, Indiana), and sanofi-aventis (Paris, France). The author would like to thank Paul Hilditch, PhD, and Catherine Jones, PhD (Watermeadow Medical, Witney, Oxfordshire, United Kingdom), for assistance with manuscript preparation.
REFERENCES 1. Nesher R, Cerasi E. Modeling phasic insulin release: Immediate and time-dependent effects of glucose. Diabetes. 2002;51(Suppl 1):S53–S59. 2. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW. Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes. 1988;37:736–744. 3. Heinemann L, Traut T, Heise T. Time-action profile of inhaled insulin. Diabet Med. 1997;14:63–72. 4. Nosek L, Heinemann L, Kaiser M, et al. No increase in the duration of action with rising doses of insulin aspart. Diabetes. 2003;52(Suppl 1):A128. Abstract. 5. Overmann H, Heinemann L. Injection-meal interval: Recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract. 1999;43:137–142. 6. Brunner GA, Hirschberger S, Sendlhofer G, et al. Postprandial administration of the insulin analogue insulin aspart in patients with type 1 diabetes mellitus. Diabet Med. 2000;17:371–375. 7. Berger M. Towards more physiological insulin therapy in the 1990s. A comment. Diabetes Res Clin Pract. 1989;6:S25– S31. 8. Brange J, Volund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev. 1999;35:307– 335.
Volume 29 Supplement D
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T. Heise 9. Heinemann L, Woodworth JR. Insulin lispro. Chapter III: Pharmacokinetics and metabolism of insulin lispro. Drugs Today. 1998;34 (Suppl C):23–36. 10. Heinemann L, Heise T, Wahl LC, et al. Prandial glycaemia after a carbohydrate-rich meal in type 1 diabetic patients: Using the rapid acting insulin analogue (Lys[B28], Pro[B29]) human insulin. Diabet Med. 1996;13:625–629. 11. Muhlhauser I, Toth G, Sawicki PT, Berger M. Severe hypoglycemia in type 1 diabetic patients with impaired kidney function. Diabetes Care. 1991;14:344–346. 12. Bending JJ, Pickup JC, Viberti GC, Keen H. Glycaemic control in diabetic nephropathy. Br Med J (Clin Res Ed). 1984;288:1187–1191. 13. Rave K, Heise T, Pfutzner A, et al. Impact of diabetic nephropathy on pharmacodynamic and pharmacokinetic properties of insulin in type 1 diabetic patients. Diabetes Care. 2001; 24:886–890. 14. Pettitt DJ, Ospina P, Kolaczynski JW, Jovanovic L. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care. 2003;26:183–186. 15. Mathiesen ER, Kinsley B, Amiel SA, et al, for the Insulin Aspart Pregnancy Study Group. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: A randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care. 2007;30: 771–776. 16. Hod M, Damm P, Kaaja R, et al. Fetal and perinatal outcomes in type 1 diabetes pregnancy: A randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol. 2007; Sept 29 [Epub ahead of print]. doi:10.1016/j.ajog.2007.08.005. 17. Jovanovic L, Giammattei J, Acquistapace M, et al. Efficacy comparison between preprandial and postpran-
2007
dial insulin aspart administration with dose adjustment for unpredictable meal size. Clin Ther. 2004;26: 1492–1497. 18. Schernthaner G, Wein W, Sandholzer K, et al. Postprandial insulin lispro. A new therapeutic option for type 1 diabetic patients. Diabetes Care. 1998;21:570–573. 19. Krones R, Heise T, Basir S, et al. Time-action profiles of insulin aspart and human regular insulin in elderly and middle-aged subjects with
type 2 diabetes. Diabetes. 2004;53 (Suppl 2):A133. Abstract. 20. Mortensen HB, Lindholm A, Olsen BS, Hylleberg B. Rapid appearance and onset of action of insulin aspart in paediatric subjects with type 1 diabetes. Eur J Pediatr. 2000;159:483– 488. 21. Holmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol. 2005;60:469–476.
Address correspondence to: Tim Heise, MD, Profil Institut für Stoffwechselforschung GmbH, Hellersbergstraße 9, D-41460, Neuss, Germany. E-mail: [email protected] S165
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Getting Closer to Physiologic Insulin Secretion Tim Heise, MD Profil Institute for Metabolic Research, Neuss, Germany
ABSTRACT
INTRODUCTION
Background: The goal of insulin replacement therapy in diabetes mellitus (DM) is to recreate a normal physiologic insulin supply throughout the day. Objective: This article reviewed the use of rapidacting insulin analogues in recreating physiologic postprandial insulin responses. Methods: This review article was based on a presentation at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues” that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. Results: In the context of mealtime insulin supply, recreating physiologic postprandial insulin responses requires rapid availability of insulin within a short time of eating and a duration of action that does not extend into the late postprandial period. Conventional human insulin is not ideally suited to SC injection, with its slow onset of action and dose-dependent duration of action. The rapid-acting insulin analogues have been designed to address these deficiencies, with more rapid onset of action, higher maximal effects, and consequently better postprandial glycemic control. These properties have been reported in patients with type 1 and type 2 DM, as well as in nondiabetic individuals in euglycemic clamp studies. Rapid-acting insulin analogues are also of particular interest in people with diabetic nephropathy, women with gestational DM, and elderly patients with DM. Conclusions: Compared with soluble human (regular) insulin, rapid-acting insulin analogues have a more rapid onset of action and a shorter duration of action. Their potential in special patient groups is now being established in clinical research and in everyday practice. (Clin Ther. 2007;29[Suppl D]: S161–S165) Copyright © 2007 Excerpta Medica, Inc. Key words: insulin analogues, euglycemic clamp, type 1 diabetes mellitus, type 2 diabetes mellitus, insulin aspart.
A swift response is essential when seeking to match physiologic insulin supply. The nondiabetic individual responds to a glucose load with a prompt first-phase insulin response that is blunted or absent in individuals with type 2 diabetes mellitus (DM).1 The effect on glycemic control of replacing early prandial insulin has been described in detail by Bruce et al.2 Insulin was administered intravenously to 8 patients with type 2 DM (mean [SD] age, 62.0 [6.8] years; 7 males, 1 female); 9 nondiabetic individuals (mean [SD] age, 59.2 [8.3] years; 6 males, 3 females) were used as controls. When the total dose of insulin (1.8 U) was delivered within 30 minutes of a mixed meal (breakfast cereal, 30 g; milk, 150 mL; orange juice, 150 mL; 2 slices of toast, 30 g each; butter, 10 g; 2 cups of decaffeinated coffee), the peak glucose increment was reduced to a level similar to the nondiabetic controls; however, if the same insulin dose was delivered between 30 and 60 minutes after the meal, or administered evenly over 180 minutes, glycemic response to the meal was unimproved, showing the importance of insulin availability during the early postprandial period. The purpose of this article was to review the use of rapid-acting insulin analogues in meeting the goal of recreating physiologic postprandial insulin responses.
2007
METHODS This review was based on a presentation at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues” that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa.
Accepted for publication November 7, 2007. doi:10.1016/j.clinthera.2007.12.012 0149-2918/$32.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2007 Excerpta Medica, Inc.
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LIMITATIONS OF CONVENTIONAL EXOGENOUS INSULIN THERAPY Exogenous insulin is not delivered intravenously in everyday life, and conventional SC insulin cannot replicate its speed of action. Heinemann et al3 compared the time–action profiles of IV and SC regular insulin in a euglycemic clamp study in 12 healthy male volunteers (mean [SD] age, 25 [2] years). Onset of action was much slower with subcutaneously injected insulin: mean half-maximal effect was reached after 54 minutes compared with 7 minutes for IV insulin, and mean maximal effect was reached after 147 minutes and 14 minutes with SC and IV insulin, respectively. The limitation of subcutaneously administered conventional insulin becomes even more apparent with higher doses. Nosek et al,4 in a 6-way crossover euglycemic clamp study in 14 healthy volunteers (mean [SD] age, 28 [4] years; 10 males, 4 females), examined the dose dependency of the pharmacodynamics of 6, 12, and 24 U of conventional soluble human insulin. They reported a significant increase in the duration of action with higher doses, indicated by a significant increase in total glucose infusion requirement from 6 to 12 hours (P < 0.05). As a consequence of its onset of action and varying duration of action, conventional insulin may be incapable of adequately controlling postprandial glucose excursions; this problem means that soluble human insulin has to be injected several minutes before a meal. However, patients often fail to use an adequate injection– meal interval,5 which further negatively impacts postprandial glucose control. This was illustrated in a study by Brunner et al6 of 20 patients (mean [SD] age, 36.4 [11.2] years; 12 males, 8 females) with type 1 DM. Peak postprandial glucose concentrations were 13.3 mmol/L with human insulin, injected 15 minutes before a test meal; these concentrations worsened to 14.1 mmol/L when the insulin was injected at the time of the meal.
RAPID-ACTING INSULIN ANALOGUES The limitations of conventional insulin, and the need for insulins with improved pharmacodynamics, have been recognized for some years,7 and several modified insulins have been produced. Three rapid-acting insulin analogues are available: insulin lispro (Lys[B28], Pro[B29] human insulin), insulin aspart (Asp[B28] human insulin), and insulin glulisine (Lys[B3], Glu[B29] human insulin). These molecules were deS162
signed to reduce both the time to onset of metabolic effect and the duration of that effect by weakening the associative interactions between insulin monomers, thus enabling more rapid dissociation of insulin hexamers, compared with human insulin, after SC injection.8 Compared with soluble human (regular) insulin, rapid-acting insulin analogues have a more rapid onset of action and a shorter duration of action. In the study by Nosek et al,4 no significant increase in late metabolic activity (beyond 6 hours postdosing) was observed when insulin aspart doses of 6, 12, and 24 U were compared. All doses of insulin aspart showed higher maximal effects, and more rapid onset of action, than corresponding doses of soluble human insulin, with significantly lower (P < 0.05) total glucose infusion from 6 to 12 hours postdose (Figure). Similar results have also been reported for insulin lispro.9 Therefore, rapid-acting insulin analogues, such as insulin aspart, are able to control postprandial glucose excursions to a greater extent than soluble human insulin, even when the latter is dosed several minutes preprandially, as found in the study by Brunner et al.6 In this study of patients with type 1 DM, maximum plasma glucose levels after a test meal were significantly lower with insulin aspart dosed at the time of the meal (11.2 mmol/L) than with human insulin dosed at the time of the meal or 15 minutes before the meal (13.3 and 14.1 mmol/L, respectively; both, P < 0.05 vs insulin aspart). This advantage of the modern rapid-acting insulin analogue is especially evident when a high-carbohydrate meal is consumed. Heinemann et al10 investigated postprandial glycemia in 10 type 1 DM patients (mean [SD] age, 29 [3] years) after they had consumed a “fast-food” meal of pizza, cola, and carbohydraterich dessert. Comparison of insulin lispro with soluble human insulin showed a 22% reduction in total blood glucose excursion (1.76 vs 2.26 mmol/L · 240 min; P < 0.01) and lower maximal glucose concentrations (9.9 vs 11.9 mmol/L; P < 0.05).
SPECIAL PATIENT GROUPS The improved pharmacodynamics of rapid-acting insulin analogues are of value in DM management in general because they provide a better approximation to normal physiologic insulin release. In addition, there are a number of special patient groups that might benefit in particular from their use: these inVolume 29 Supplement D
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Page S163
T. Heise
Insulin aspart Soluble human insulin
2100 1900
GIR AUC 6–12 h (mg/kg)
161_heise
†
†
1700 1500
*
*
*
1300 1100 900 0 6
12
24
Insulin Dose (U) Figure. Time–action characteristics (glucose infusion rates [GIR] 6–12 hours after dosing) of the rapid-acting insulin analogue insulin aspart and soluble human insulin, at doses of 6, 12, and 24 U, in healthy volunteers. Values are given as mean (SD). *P < 0.05 for insulin aspart versus soluble human insulin; †P < 0.05 for soluble human insulin versus 24 U of soluble human insulin. Data from Nosek et al.4
clude individuals with diabetic nephropathy, women with gestational DM, and elderly patients with DM.
Patients with Diabetic Nephropathy Diabetic nephropathy tends to prolong the duration of action of insulin, due to reduced renal insulin clearance; individuals with nephropathy may therefore be at increased risk of hypoglycemia and poorer metabolic control.11,12 Rave et al13 found that insulin lispro had a shorter duration of action than conventional soluble human insulin in patients with diabetic nephropathy. In this euglycemic clamp study of 12 patients (mean [SD] age, 41 [5] years; 6 males, 6 females) with type 1 DM and proteinuria >500 mg/24 h and/or serum creatinine >1.5 mg/dL, mean peak insulin levels were higher (359 vs 213 pmol/L; P < 0.05) and mean time to maximum insulin levels shorter (85 vs 118 minutes; P < 0.05) after injection of insulin lispro versus injection of soluble human insulin, respectively. Mean maximal metabolic effect (as measured by the glucose infusion rate) was higher with insulin lispro than with soluble human insulin (5.4 vs 3.4 mg/kg · min; P < 0.003) and was achieved earlier (102 vs 191 minutes; P < 0.003). Importantly, mean du2007
ration of action (assessed by time to late half-maximal metabolic effect) was also significantly shorter with insulin lispro than with soluble human insulin (244 vs 343 minutes; P < 0.003). The faster onset of action and shorter duration of action of rapid-acting insulin analogues could therefore achieve acceptable glucose control without an increased risk of hypoglycemia, especially in people with diabetic nephropathy.
Women with Gestational Diabetes Mellitus For women with gestational DM, it is important for them to reach acceptable—and even normal, if possible—levels of glucose control (including postprandial glucose concentrations comparable to those in healthy people) to reduce the risk of adverse maternal and fetal outcomes. Therefore, women with gestational DM may benefit from using rapid-acting insulin analogues to achieve better postprandial glucose control. Pettitt et al14 reported in 15 women with gestational DM that insulin aspart, given 5 minutes before the meal, significantly reduced postprandial glucose excursions (mean glucose AUC at 180 minutes, 7.1 [7.9] mg 䡠 h 䡠 dL–1; P = 0.018 vs no insulin), whereas soluble human insulin, injected 30 minutes preprandiS163
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Clinical Therapeutics ally, was unable to significantly reduce postprandial glucose excursions versus no exogenous insulin (mean glucose AUC at 180 minutes, 30.2 [6.1] mg 䡠 h 䡠 dL–1; P = 0.997). Based on C-peptide measurements, administration of insulin aspart reduced the demand for endogenous insulin after the meal. Because insulin aspart has been approved for use in pregnancy, this analogue might be an option to improve postprandial glucose excursions and thereby maternal and fetal outcomes in pregnancies affected by DM.15,16
CONCLUSIONS Modern rapid-acting insulin analogues were developed to more closely mimic physiologic postprandial insulin responses. Because of their faster onset of action and their shorter duration of action, these agents can effectively control postprandial glucose excursions significantly better than soluble human insulin. Their potential in special patient groups is now being established in clinical research and in everyday practice.
ACKNOWLEDGMENTS Elderly Patients with Diabetes Mellitus Rapid-acting insulin analogues are also of particular interest in patient groups with unpredictable eating habits, such as the elderly. Unlike conventional insulin, insulin aspart can be injected postprandially without loss of postprandial glucose control.6,17 In a study of 19 patients with type 1 DM (age range, 22–82 years), postprandial glucose excursions were not significantly different when insulin aspart was injected 0 to 5 minutes before the start of, or immediately after, a test meal (baseline-adjusted postprandial excursion, 4487 and 5751 mg/dL · min, respectively).17 Similar results have been obtained with insulin lispro.18 The use of insulin analogues in elderly patients has not been extensively studied; however, the pharmacodynamics of insulin aspart and soluble human insulin were compared by Krones et al19 in a euglycemic clamp study of 19 elderly subjects (mean age, 70 years) with type 2 DM. They determined that, in accordance with results found in other patient groups (eg, children and adolescents with type 1 DM,20 patients with type 1 DM and renal or hepatic impairment21), insulin aspart had a faster onset of action than soluble human insulin (glucose infusion 0–2 hours, 265 vs 112 mg/kg; P < 0.05) and a shorter duration of action (time to late half-maximal action, 348 vs 497 minutes, respectively). Although more clinical evidence is needed, the pharmacodynamic characteristics of insulin aspart in elderly patients which are similar to those in younger patients suggest that postprandial administration of this agent has the potential to be successful in the elderly population. This should allow titration of insulin according to the real—rather than the expected—carbohydrate intake, thereby minimizing the risk of postprandial hypoglycemia in patients with unpredictable eating habits. S164
The publication of this article was supported by Novo Nordisk A/S (Bagsværd, Denmark). The author has received research grants and honoraria for presentations and participation in advisory boards from several pharmaceutical companies, including the insulin-producing companies Novo Nordisk A/S, Eli Lilly and Company (Indianapolis, Indiana), and sanofi-aventis (Paris, France). The author would like to thank Paul Hilditch, PhD, and Catherine Jones, PhD (Watermeadow Medical, Witney, Oxfordshire, United Kingdom), for assistance with manuscript preparation.
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Address correspondence to: Tim Heise, MD, Profil Institut für Stoffwechselforschung GmbH, Hellersbergstraße 9, D-41460, Neuss, Germany. E-mail: [email protected] S165