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Current eNewsletter

 
 
June 2010 eNewsletter
The interaction between insulin analogs and receptors: Are there risks?
 
Understanding insulin therapies and the IGF-1 receptor
As a clinician who treats diabetes, you may be concerned about the possibility of a link between insulin and cancer. The issue was brought to the forefront last summer, when several analyses were published that suggested an increase in cancer diagnosis in patients taking a specific basal insulin analog.1-5 Ongoing discussions continue around the topic of insulin structure, its impact on insulin-like growth factor-1 receptor (IGF-1R), and the possible link between this affinity and mitogenicity. If a link does exist, the mechanism may involve mitogenesis mediated by the receptor for insulin-like growth factor-1 (IGF-1).6-9
The metabolic and mitogenic properties of insulin analogs depend on their interactions with two receptors: the insulin receptor, which mediates the desired metabolic effects, and the structurally similar IGF-1 receptor (IGF-1R).1,10,11 It is theorized that mitogenicity can result from prolonged activation of the insulin receptor or from activation of the IGF-1 receptor, so understanding binding properties is essential in developing insulin analogs.7,12,13
For many years, Novo Nordisk has understood the importance of molecular safety—ensuring that structural modifications from human insulin do not unfavorably affect receptor binding. All new Novo Nordisk insulin analogs are assessed during development for their interactions with the insulin and IGF-1 receptors, and no analog can progress to clinical development without first demonstrating a profile equivalent to, or favorable to, that of human insulin.14
Learn more at NovoMedLink.com
Several published analyses have given some doctors a cause for concern.
 
Levemir® and IGF-1R affinity: a closer look
With molecular safety in mind at all times, Novo Nordisk engineered Levemir® for low IGF-1R affinity.6,13 Levemir® contains a fatty-acid side chain that helps prolong its metabolic activity in the body but may also reduce IGF-1R affinity, by reducing positive charge at the point of attachment.6 And because Levemir® is highly bound to albumin in the bloodstream, less of the active molecule may be available for binding to IGF-1R.6
Learn more about low Levemir® affinity for the IGF-1 receptor relative to human insulin and the results of observational data related to the incidence of cancer diagnosis in patients with diabetes taking Levemir®.6,15
 
The ADA/ACS
Statement on
Diabetes and
Cancer Risk
The recent American Diabetes Association/American Cancer Society consensus report on diabetes and cancer risk examines the links between diabetes, including diabetes risk factors and diabetes treatment, and cancer. With molecular safety in mind at all times Novo Nordisk endeavors to design medications that minimize treatment risk and maximize positive outcomes for patients.
 
The proven weight benefits of Levemir®
Weight gain is often a major concern for patients and physicians initiating insulin therapy.16 When starting basal insulin for patients with type 2 diabetes, Levemir® can offer real-world weight benefits.17,18*
•
In a 52-week clinical study, patients with type 2 diabetes gained 26% less weight with Levemir® than with insulin glargine18
•
A retrospective analysis showed weight benefits for overweight or obese patients with type 2 diabetes when starting Levemir®19
•
Less weight gain was confirmed in 12 of 12 controlled clinical trials20
 
This e-mail is just one of the many resources available to registered members of NovoMedLink™.
To find even more relevant information for you and your practice, visit NovoMedLink.com. 
 
Levemir® (insulin detemir [rDNA origin] injection)
Indications and Usage
Levemir® is indicated for once- or twice-daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.
Levemir® Important Safety Information
Levemir® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.
Levemir® should not be diluted or mixed with any other insulin preparations.
Hypoglycemia is the most common adverse effect of all insulin therapies, including Levemir®. As with other insulins, the timing of hypoglycemic events may differ among various insulin preparations. Glucose monitoring is recommended for all patients with diabetes. Levemir® is not to be used in insulin infusion pumps. Any change of insulin dose should be made cautiously and only under medical supervision. Concomitant oral antidiabetes treatment may require adjustment.
Needles and Levemir® FlexPen® must not be shared.
Inadequate dosing or discontinuation of treatment may lead to hyperglycemia and, in patients with type 1 diabetes, diabetic ketoacidosis. Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Dose and timing of administration may need to be adjusted to reduce the risk of hypoglycemia in patients being switched to Levemir® from other intermediate or long-acting insulin preparations. The dose of Levemir® may need to be adjusted in patients with renal or hepatic impairment.
Other adverse events commonly associated with insulin therapy may include injection site reactions (on average, 3% to 4% of patients in clinical trials) such as lipodystrophy, redness, pain, itching, hives, swelling, and inflammation. Less common but more serious are severe cases of generalized allergy, including anaphylactic reaction, which may be life threatening.
*Whether these observed differences represent true differences in the effects of Levemir®, NPH insulin, and insulin glargine is not known, since these trials were not blinded and the protocols (eg, diet and exercise instructions and monitoring) were not specifically directed at exploring hypotheses related to weight effects of the treatments compared. The clinical significance of the observed differences in weight has not been established.
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Novo Nordisk Disclaimer
These materials are provided "as is" and without warranties of any kind either express or implied. To the fullest extent permissible, pursuant to applicable law, we disclaim all warranties, express or implied, including, but not limited to, implied warranties of merchantability and fitness for a particular purpose. We do not warrant that the functions contained on any Novo Nordisk Inc. site will be uninterrupted or error-free, that defects will be corrected or that any Novo Nordisk Inc. site or the servers that make such materials available are free of viruses or other harmful components. We do not warrant or make any representations regarding the use or the results of the use of the materials on any Novo Nordisk Inc. site in terms of their correctness.
 
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References:
1. Smith U, Gale EA. Does diabetes therapy influence the risk of cancer? Diabetologia. 2009;52(9):1699-1708.
 
2. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52(9):1732-1744.
 
3. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden. Diabetologia. 2009;52(9):1745-1754.
 
4. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52(9):1766-1777.
 
5. Colhoun HM; SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52(9):1755-1765.
 
6. Kurtzhals P, Schäffer L, Sørensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49(6):999-1005.
 
7. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4(7):505-518.
 
8. Slieker LJ, Brooke GS, DiMarchi RD, et al. Modifications in the B10 and B26-30 regions of the B chain of human insulin alter affinity for the human IGF-I receptor more than for the insulin receptor. Diabetologia. 1997;40(suppl 2):S54-S61.
 
9. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;1076:873-877.
 
10. Kjeldsen T, Andersen AS, Wiberg FC, et al. The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site. Proc Natl Acad Sci U S A. 1991;88(10):4404-4408.
 
11. Kristensen C, Andersen AS, Hach M, Wiberg FC, Schäffer L, Kjeldsen T. A single-chain insulin-like growth factor I/insulin hybrid binds with high affinity to the insulin receptor. Biochem J. 1995;305(pt 3):981-986.
 
12. Hansen BF, Danielsen GM, Drejer K, et al. Sustained signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochem J. 1996;315(pt 1):271-279.
 
13. Kurtzhals P. Pharmacology of insulin detemir. Endocrinol Metab Clin North Am. 2007;36(suppl 1):14-20.
 
14. Gammeltoft S, Hansen BF, Dideriksen L, et al. Insulin aspart, a novel rapid-acting human insulin analogue. Expert Opin Investig Drugs. 1999;8(9):1431-1442.
 
15. Dejgaard A, Lynggaard H, Råstam J, Krogsgaard Thomsen M. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia. 2009;52(12):2507-2512.
 
16. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord. 2002;26(suppl 3):S18-S24.
 
17. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomized, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia. 2008;51(3):408-416.
 
18. Hollander P, Cooper J, Bregnhøj J, Pedersen CB. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther. 2008;30(11):1976-1987.
 
19. Philis-Tsimikas A, Koenen C, Pederson CB, Thorsteinsson B. Use of insulin detemir once-daily results in less weight gain compared with the use of NPH insulin, particularly in obese subjects with type 2 diabetes [abstract 0979]. Diabetologia. 2007;50(suppl 1):S404.
 
20. Data on file. NDA21-536. Novo Nordisk, Inc., Princeton, NJ.
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
FlexPen® and Levemir® are registered trademarks of Novo Nordisk A/S. NovoMedLink™ is a trademark of Novo Nordisk A/S.
©2010 Novo Nordisk A/S. All rights reserved.
141606     July  2010

  1. Levemir® (insulin detemir [rDNA origin] injection) Indications and Usage

    Levemir® is indicated for once- or twice-daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

    Levemir® Important Safety Information

    Levemir® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.

    Levemir® should not be diluted or mixed with any other insulin preparations.

    Hypoglycemia is the most common adverse effect of all insulin therapies, including Levemir®. As with other insulins, the timing of hypoglycemic events may differ among various insulin preparations. Glucose monitoring is recommended for all patients with diabetes. Levemir® is not to be used in insulin infusion pumps. Any change of insulin dose should be made cautiously and only under medical supervision. Concomitant oral antidiabetes treatment may require adjustment.

    Needles and Levemir® FlexPen® must not be shared.

    Inadequate dosing or discontinuation of treatment may lead to hyperglycemia and, in patients with type 1 diabetes, diabetic ketoacidosis. Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Dose and timing of administration may need to be adjusted to reduce the risk of hypoglycemia in patients being switched to Levemir® from other intermediate or long-acting insulin preparations. The dose of Levemir® may need to be adjusted in patients with renal or hepatic impairment.

    Other adverse events commonly associated with insulin therapy may include injection site reactions (on average, 3% to 4% of patients in clinical trials) such as lipodystrophy, redness, pain, itching, hives, swelling, and inflammation. Less common but more serious are severe cases of generalized allergy, including anaphylactic reaction, which may be life threatening.

    *Whether these observed differences represent true differences in the effects of Levemir®, NPH insulin, and insulin glargine is not known since these trials were not blinded and the protocols (e.g., diet and exercise instructions and monitoring) were not specifically directed at exploring hypotheses related to weight effects of the treatments compared. The clinical significance of the observed differences in weight has not been established.

    Please see Prescribing InformationPrescribing Information.

  2. NovoLog® (insulin aspart [rDNA origin] injection) Indications and Usage

    NovoLog® is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

    NovoLog® Important Safety Information

    NovoLog® is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog® or one of its excipients.

    NovoLog® has a more rapid onset and shorter duration of action than regular human insulin. An injection of NovoLog® should be immediately followed by a meal within 5 to 10 minutes. Because of the short duration of action of NovoLog®, a longer-acting insulin also should be used in patients with type 1 diabetes and may be needed in patients with type 2 diabetes. When used in an external subcutaneous insulin infusion pump, NovoLog® should not be mixed with any other insulin or diluent. Hypoglycemia is the most common adverse effect of all insulin therapies, including NovoLog®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulins.

    Any change of insulin dose should be made cautiously and only under medical supervision. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using external pump infusion therapy. As with all insulin preparations, the time course of action of NovoLog® may vary in different individuals or at different times in the same individual and is dependent on many conditions, including injection site, local blood supply, temperature, and level of physical activity.

    Needles and NovoLog® FlexPen® must not be shared.

    NovoLog® has not been studied in children with type 2 diabetes or in children with type 1 diabetes under the age of two.

    Severe, life-threatening generalized allergy, including anaphylactic reaction, may occur with any insulin product, including NovoLog®. Adverse reactions observed with NovoLog® include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus. Insulin, particularly when given intravenously or in settings of poor glycemic control, may cause hypokalemia. Like all insulins, NovoLog® requirements may be reduced in patients with renal impairment or hepatic impairment.

    All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy.

    Please see Prescribing InformationPrescribing Information.

  3. NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, [rDNA origin]) Indications and Usage

    NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, [rDNA origin]) is an insulin analog indicated to improve glycemic control in patients with diabetes mellitus.

    Important Limitations of Use:
    In premix insulins, such as NovoLog® Mix 70/30, the proportions of rapid acting and long acting insulins are fixed and do not allow for basal versus prandial dose adjustments.

    NovoLog® Mix 70/30 Important Safety Information

    NovoLog® Mix 70/30 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog® Mix 70/30 or one of its excipients.

    NovoLog® Mix 70/30 has a faster onset of action than human insulin premix 70/30 and should be dosed within 15 minutes before meal initiation for patients with type 1 diabetes. For patients with type 2 diabetes, dosing should occur within 15 minutes before or after meal initiation.

    NovoLog® Mix 70/30 should not be administered intravenously or used in insulin infusion pumps. NovoLog® Mix 70/30 should not be mixed with any other insulin product.

    Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog® Mix 70/30. The timing of hypoglycemia may reflect the time-action profile of the insulin formulation. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin should be made cautiously and only under medical supervision.

    Needles and NovoLog® Mix 70/30 FlexPen® must not be shared.

    Severe, life-threatening generalized allergy, including anaphylaxis, may occur with insulin products, including NovoLog® Mix 70/30. Adverse reactions observed with NovoLog® Mix 70/30 include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus. Insulin, particularly when given in settings of poor glycemic control, may cause hypokalemia. Like all insulins, NovoLog® Mix 70/30 requirements may be reduced in patients with renal impairment or hepatic impairment.

    The safety and effectiveness of NovoLog® Mix 70/30 has not been established in pediatric patients. Clinical studies of NovoLog® Mix 70/30 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

    Please see Prescribing InformationPrescribing Information.

  4. Victoza® (liraglutide [rDNA origin] injection) Indications and Usage

    Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

    Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.

    In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

    Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

    The concurrent use of Victoza® and insulin has not been studied.

    Victoza® Important Safety Information

    Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

    If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed.

    When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

    There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

    The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

    Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients.

    Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment.

    Please see Prescribing InformationPrescribing Information and Medication GuideMedication Guide.

FlexPen®, Levemir®, NovoLog®, and Victoza® are registered trademarks of Novo Nordisk A/S. NovoMedLink™ is a trademark of Novo Nordisk A/S.