Insulin Analogues
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In regard to the review of insulin analogues by Hirsch (Jan. 13 issue),1 recurrent hypoglycemia is a major impediment to the achievement of good metabolic control, as defined by the Diabetes Control and Complications Trial.2 Furthermore, asymptomatic nocturnal hypoglycemic episodes are important because they reduce counterregulation and thereby increase the risk of subsequent prolonged and severe hypoglycemia, associated occasionally with coma.3 This is particularly true for small children, who have been shown to sleep through episodes of prolonged hypoglycemia. The use of regular insulin before the evening meal leads to overinsulinization during the early part of the night, when parents most often note hypoglycemia in their children. The short-acting analogues have a clear advantage over regular insulin by reducing this risk, as has been demonstrated in a recent study in which overnight blood glucose profiles were compared with the use of two types of insulin before the evening meal.4 In our clinical setting, in which a multiple-injection insulin regimen is implemented even in toddlers, we recommend the use of the short-acting analogue before the evening meal and the use of regular insulin before breakfast and lunch, in order to allow for in-between snacks, as suggested by Hirsch.1
Angelika Mohn, M.D.
Maria Marcovecchio, M.D.
Francesco Chiarelli, M.D.
University of Chieti
66100 Chieti, Italy
amohn@unich.it
References
Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183.
The Diabetes Control and Complications Trial 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;3:615-622.
Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 1993;42:1233-1237.
Ford-Adams ME, Murphy NP, Moore EJ, et al. Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus. Diabet Med 2003;20:656-660.
To the Editor: New insulin analogues have revolutionized the treatment of diabetes mellitus in recent years. However, as Hirsch mentions, there is serious oncologic concern about some of these new substances. As compared with human insulin, glargine, a long-acting insulin analogue, has an affinity for the insulin-like growth factor (IGF) receptor that is six times as high and also increases the mitosis rate by a factor of eight in a human osteosarcoma cell line.1 Given this higher receptor affinity and the fact that high levels of circulating IGF-1 are associated with an increased risk of solid tumors2 and leukemia,3 especially in young patients, the use of glargine in children should probably be reconsidered, since this group of patients is most likely to have long-term adverse effects.
Michael C. Haffner
Marcus P. Kufner
Innsbruck Medical University
6020 Innsbruck, Austria
References
Kurtzhals P, Sch?ffer L, S?rensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005.
Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346-1353.
Petridou E, Desspyris N, Spanos E, et al. Insulin-like growth factor-I and binding protein-3 in relation to childhood leukemia. Int J Cancer 1999;80:494-496.
To the Editor: In his well-balanced review of insulin analogues, Hirsch states that "premixed insulin analogues should fill a relatively small niche for most patients who require prandial insulin, with two exceptions: those with type 2 diabetes who eat relatively small lunches and those who are unable to use more sophisticated regimens." This statement ignores an important issue: premixed insulin is the most widely used insulin formulation.1 Furthermore, 46 percent of patients with type 2 diabetes can achieve the glycosylated hemoglobin target of 6.5 percent or less with premixed analogues.2 It may appear that twice-daily premixed insulin is inferior to a more sophisticated physiological insulin substitution. However, my colleagues and I have recently shown that in a four-year study of patients with type 2 diabetes who used twice-daily premixed insulin aspart, there was a significant reduction of major hypoglycemic events and insulin needs for average-size lunches were covered, with good postprandial glucose control.3,4 Therefore, the use of premixed insulin analogues does provide an improvement in insulin therapy in a large number of patients with type 2 diabetes.
Bernhard O. Boehm, M.D.
University of Ulm
89070 Ulm, Germany
bernhard.boehm@medizin.uni-ulm.de
Dr. Boehm reports having received research grants from NovoNordisk and Aventis.
References
Mudaliar S, Edelman SV. Insulin therapy in type 2 diabetes. Endocrinol Metab Clin North Am 2001;30:935-982.
Raskin P, Rojas P, Allen E. Comparison of twice daily aspart 70/30 (BIAsp 70/30) with once-daily insulin glargine (GLA) in patients with type 2 DM on oral antidiabetic agents. Diabetes 2004;53:Suppl 2:A143-A143. abstract.
Boehm BO, Home PD, Behrend C, Kamp NM, Lindholm A. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients. Diabet Med 2002;19:393-399.
Boehm BO, Vaz JA, Brondsted L, Home PD. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Intern Med 2004;5:496-502.
Dr. Hirsch replies: Mohn and colleagues bring up an important point: the addition of insulin analogues provides us with new tools to become more creative in dealing with real-life glycemic challenges. With unrestrained creativity, there are many situations in which the use of a combination of standard insulins and analogues can resolve clinical problems. This is in contrast to the comments by Boehm, who suggests that a fixed-ratio insulin is appropriate for many patients with type 2 diabetes. Although I agree that for many patient (and perhaps physician) populations, a more sophisticated regimen of basal and prandial insulin replacement will not be successful, much of the success with a premixed regimen is based on the degree of insulin deficiency, in addition to a given patient's ability to maintain a consistent diet (in terms of both calories and the timing of the meals). Boehm and his colleagues reported that after 24 months of treatment with biphasic insulin aspart, the mean (±SE) glycosylated hemoglobin level was 8.35±0.20 percent,1 which is well above target levels in the United States and Europe.
Haffner and Kufner inquire about the increased affinity of insulin glargine for the IGF-1 receptor and the increased mitosis rate in a human osteosarcoma cell line. Although this is an understandable concern, it is reassuring that in the four years since insulin glargine was introduced in the United States, there have been no reports of acceleration of diabetic retinopathy. It should also be noted that in at least one other study in human skeletal-muscle cells, no differences in mitogenic effects were revealed between insulin glargine and human insulin.2 Since hypoglycemia is the rate-limiting factor for all insulin therapy, it seems to me that the risk-benefit ratio for the use of glargine outweighs any theoretical risk of problems not reported to date. We clearly need more data about the risk of hypoglycemia with insulin glargine as compared with neutral protein Hagedorn insulin in children. However, as I noted in my review, the risk–benefit ratio for these theoretical concerns about IGF-1–receptor binding and an increased mitosis rate is not as clear in pregnant women, and most authors would not use insulin glargine in this population.
Irl B. Hirsch, M.D.
University of Washington School of Medicine
Seattle, WA 98195-6176
ihirsch@u.washington.edu
References
Boehm BO, Vaz JA, Brondsted L, Home PD. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Intern Med 2004;5:496-502.
Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR. Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-I. J Clin Endocrinol Metab 2001;86:5838-5847.
Angelika Mohn, M.D.
Maria Marcovecchio, M.D.
Francesco Chiarelli, M.D.
University of Chieti
66100 Chieti, Italy
amohn@unich.it
References
Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183.
The Diabetes Control and Complications Trial 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;3:615-622.
Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 1993;42:1233-1237.
Ford-Adams ME, Murphy NP, Moore EJ, et al. Insulin lispro: a potential role in preventing nocturnal hypoglycaemia in young children with diabetes mellitus. Diabet Med 2003;20:656-660.
To the Editor: New insulin analogues have revolutionized the treatment of diabetes mellitus in recent years. However, as Hirsch mentions, there is serious oncologic concern about some of these new substances. As compared with human insulin, glargine, a long-acting insulin analogue, has an affinity for the insulin-like growth factor (IGF) receptor that is six times as high and also increases the mitosis rate by a factor of eight in a human osteosarcoma cell line.1 Given this higher receptor affinity and the fact that high levels of circulating IGF-1 are associated with an increased risk of solid tumors2 and leukemia,3 especially in young patients, the use of glargine in children should probably be reconsidered, since this group of patients is most likely to have long-term adverse effects.
Michael C. Haffner
Marcus P. Kufner
Innsbruck Medical University
6020 Innsbruck, Austria
References
Kurtzhals P, Sch?ffer L, S?rensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005.
Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346-1353.
Petridou E, Desspyris N, Spanos E, et al. Insulin-like growth factor-I and binding protein-3 in relation to childhood leukemia. Int J Cancer 1999;80:494-496.
To the Editor: In his well-balanced review of insulin analogues, Hirsch states that "premixed insulin analogues should fill a relatively small niche for most patients who require prandial insulin, with two exceptions: those with type 2 diabetes who eat relatively small lunches and those who are unable to use more sophisticated regimens." This statement ignores an important issue: premixed insulin is the most widely used insulin formulation.1 Furthermore, 46 percent of patients with type 2 diabetes can achieve the glycosylated hemoglobin target of 6.5 percent or less with premixed analogues.2 It may appear that twice-daily premixed insulin is inferior to a more sophisticated physiological insulin substitution. However, my colleagues and I have recently shown that in a four-year study of patients with type 2 diabetes who used twice-daily premixed insulin aspart, there was a significant reduction of major hypoglycemic events and insulin needs for average-size lunches were covered, with good postprandial glucose control.3,4 Therefore, the use of premixed insulin analogues does provide an improvement in insulin therapy in a large number of patients with type 2 diabetes.
Bernhard O. Boehm, M.D.
University of Ulm
89070 Ulm, Germany
bernhard.boehm@medizin.uni-ulm.de
Dr. Boehm reports having received research grants from NovoNordisk and Aventis.
References
Mudaliar S, Edelman SV. Insulin therapy in type 2 diabetes. Endocrinol Metab Clin North Am 2001;30:935-982.
Raskin P, Rojas P, Allen E. Comparison of twice daily aspart 70/30 (BIAsp 70/30) with once-daily insulin glargine (GLA) in patients with type 2 DM on oral antidiabetic agents. Diabetes 2004;53:Suppl 2:A143-A143. abstract.
Boehm BO, Home PD, Behrend C, Kamp NM, Lindholm A. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients. Diabet Med 2002;19:393-399.
Boehm BO, Vaz JA, Brondsted L, Home PD. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Intern Med 2004;5:496-502.
Dr. Hirsch replies: Mohn and colleagues bring up an important point: the addition of insulin analogues provides us with new tools to become more creative in dealing with real-life glycemic challenges. With unrestrained creativity, there are many situations in which the use of a combination of standard insulins and analogues can resolve clinical problems. This is in contrast to the comments by Boehm, who suggests that a fixed-ratio insulin is appropriate for many patients with type 2 diabetes. Although I agree that for many patient (and perhaps physician) populations, a more sophisticated regimen of basal and prandial insulin replacement will not be successful, much of the success with a premixed regimen is based on the degree of insulin deficiency, in addition to a given patient's ability to maintain a consistent diet (in terms of both calories and the timing of the meals). Boehm and his colleagues reported that after 24 months of treatment with biphasic insulin aspart, the mean (±SE) glycosylated hemoglobin level was 8.35±0.20 percent,1 which is well above target levels in the United States and Europe.
Haffner and Kufner inquire about the increased affinity of insulin glargine for the IGF-1 receptor and the increased mitosis rate in a human osteosarcoma cell line. Although this is an understandable concern, it is reassuring that in the four years since insulin glargine was introduced in the United States, there have been no reports of acceleration of diabetic retinopathy. It should also be noted that in at least one other study in human skeletal-muscle cells, no differences in mitogenic effects were revealed between insulin glargine and human insulin.2 Since hypoglycemia is the rate-limiting factor for all insulin therapy, it seems to me that the risk-benefit ratio for the use of glargine outweighs any theoretical risk of problems not reported to date. We clearly need more data about the risk of hypoglycemia with insulin glargine as compared with neutral protein Hagedorn insulin in children. However, as I noted in my review, the risk–benefit ratio for these theoretical concerns about IGF-1–receptor binding and an increased mitosis rate is not as clear in pregnant women, and most authors would not use insulin glargine in this population.
Irl B. Hirsch, M.D.
University of Washington School of Medicine
Seattle, WA 98195-6176
ihirsch@u.washington.edu
References
Boehm BO, Vaz JA, Brondsted L, Home PD. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Intern Med 2004;5:496-502.
Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR. Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-I. J Clin Endocrinol Metab 2001;86:5838-5847.