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This article originally posted 11 April, 2006 and appeared in  Issue 307

It’s not just another glargine Levemir®

Levemir®’s prolonged action (up to 24 hours) is achieved by a novel principle, totally different than any other long acting insulin
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Levemir® (insulin detemir [rDNA origin] injection, Novo Nordisk Inc.) is a new long-acting, basal insulin analog Levemir® was approved for use in Europe in June 2004 and subsequently received FDA approval in June 2005. Levemir® was launched in the United States on March 27, 2006.

Levemir® is produced by recombinant DNA technology using Saccharomyces cerevisiae, commonly known as baker’s yeast, followed by chemical modification. Like any insulin, Levemir® stimulates glucose uptake in target tissues. Unlike the other available basal formulations, NPH insulin and Lantus® (insulin glargine [rDNA origin] injection, Aventis Pharmaceuticals Inc.), Levemir® is soluble at a neutral pH. Levemir®’s prolonged action (up to 24 hours) is achieved by a novel principle. A myristic acid moiety, acylated to the B29 lysine contributes to extending action by 1) promoting increased self-association of Levemir® molecules in the subcutaneous depot, and 2) binding to albumin at the injection site and in the circulation. {Havelund, 2004; Kurtzhals, 2004} Dissociated Levemir® molecules can readily enter the circulation, where they reversibly bind albumin, further delaying distribution to target tissues. {Markussen, 1996} In vitro studies have demonstrated no clinically relevant interactions between Levemir® and other albumin-bound drugs. {Kurtzhals, 2004; Kurtzhals, 1997}

Data from pharmacodynamic studies demonstrate that Levemir® has a relatively flat action profile with a duration of action of up to 24 hours. {Plank, 2005}. Steady-state levels of Levemir® are reached after 2-3 days, depending on dosage amount and frequency. {Bott, 2003} No differences in pharmacokinetic profiles have been observed between children and adolescents and adults with type 1 diabetes, different race/ethnicities, or between individuals with either normal or impaired renal or hepatic function. {Levemir® PI, 2005}

Because Levemir® is soluble, resuspension prior to injection is not required as with NPH insulin, and it does not form a precipitate upon injection as with Lantus®, thereby eliminating two potential sources of variation in action. In addition, albumin binding in both the circulation and interstitial fluid has been proposed to provide a buffering effect against the impact of changes in absorption rate, further contributing to more predictable activity. {Kurtzhals, 2004} Levemir® has demonstrated a more consistent blood glucose-lowering response compared to NPH insulin and Lantus®. In a study of 54 individuals with type 1 diabetes, within-patient variability for glucose infusion rate (GIR) was found to be significantly less with Levemir® compared with NPH and Lantus®. {Heise, 2004}

Levemir® has demonstrated glycemic control similar to NPH insulin in patients with type 2 diabetes inadequately controlled on OADs {Hermansen, 2004}, as well as on basal-bolus therapy. {Haak, 2005; Raslova, 2004} In the study of 475 insulin-naïve patients inadequately controlled on OADs and transitioned to twice-daily Levemir® or NPH insulin, 70% of patients on Levemir® reached an HbA1C=7% after 24 weeks of following a goal-directed titration protocol. Further, more patients on Levemir® achieved an HbA1C=7% without hypoglycemia compared to NPH insulin (26% vs. 16%, respectively; P<0.01). Effective glycemic control has also been observed with Levemir® in patients with type 1 diabetes. {Home, 2006}

Levemir®’s more consistent blood glucose response has been mathematically correlated to a reduced risk of hypoglycemia in patients, i.e., a patient would experience twice the normal insulin effect (potential risk of hypoglycemia) about every second year with Levemir®, 10 times a year with Lantus®, and 24 times a year with NPH insulin. {Heise, 2004} In fact, effective glycemic control with a reduced risk of hypoglycemia (particularly nocturnal hypoglycemia) has been a consistent finding in clinical trials with Levemir®, in both type 1 and type 2 diabetes. A recent meta-analysis of 4 clinical trials of adult patients with type 1 diabetes reported a 22% lower risk of overall hypoglycemia with Levemir® compared with NPH insulin (P < .001). {Russell Jones, 2005} The results also demonstrated that the extent of risk reduction for hypoglycemia with Levemir® compared to NPH increased with improving HbA1C. In a study comparing Levemir® with Lantus®, in combination with pre-meal insulin aspart, among patients with type 1 diabetes, Levemir® was associated with a 72% lower risk of major hypoglycemia and a 32% lower risk of nocturnal hypoglycemia compared to Lantus® (P < .05 for both comparisons). {Pieber, 2005} Similarly, in the study of Levemir® or NPH added to oral agents in patients with type 2 diabetes, Levemir® was associated with a 47% lower risk of overall hypoglycemia and a 55% lower risk of nocturnal hypoglycemia compared to NPH insulin (P < .001). {Hermansen, 2004}

Levemir® has consistently demonstrated less weight gain compared to NPH insulin in clinical trials (12 of 12 clinical trials) in both type 1 and type 2 diabetes. {Home, 2006; Roberts, 2001} In studies of type 1 diabetes, patients using Levemir® maintained their weight or experienced a minor weight loss, while patients using NPH gained weight. {Home, 2006} Studies of patients with type 2 diabetes have reported less weight gain with Levemir® (up to 2.6 lbs) than with NPH insulin (up to 6.2 lbs). {Hermansen, 2004; Home, 2006} The mechanisms behind the favorable weight effects of Levemir® are being investigated. {Hennige, 2005; Hordern, 2005}

Levemir® can be administered once- or twice-daily. For insulin naïve patients who are inadequately controlled on OADs, Levemir® should be started at a dose of 0.1 to 0.2 U/kg once-daily in the evening or 10 units once- or twice-daily. For patients already using a basal insulin, the basal insulin can be changed to Levemir® on a unit-to-unit basis. {Levemir® PI, 2005} Levemir® is available in 10 mL vials, as well as in the Levemir® FlexPen™, which provides patients with a simple, accurate, reliable device for administration.

In summary, Levemir® provides patients with a new alternative for up to 24-hour, basal glycemic control with the added clinical benefits of less hypoglycemia and less weight gain. Furthermore, by offering a more consistent blood glucose response, Levemir® enables patients to pursue glycemic targets with less concern relating to hypoglycemia.

Complete Prescribing Information
http://www.levemir-us.com/prescribing_information.pdf

REFERENCES

Bott S, Tusek C, Jacobson L, Kristensen A, Heise T: Insulin detemir reaches steady-state after the first day of treatment and shows a peakless time-action profile with twice daily applications diabetes. Diabetes 52(Suppl 1):A112, 2003.

Haak T, Tiengo A, Draeger E, Suntum M, Waldhausl W: Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab 7:56-64, 2005.

Havelund S, Plum A, Ribel U, Jonassen I, Volund A, Markussen J, Kurtzhals P: The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharmaceutical Research 21(8):1498-1504, 2004.

Heise T, Nosek L, Ronn BB, Endahl L, Heinemann L, Kapitza C, Draeger E: Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 53:1614-1620, 2004.

Hennige AM, Metzinger E, Fritsche A, Haring H-A: Tissue selectively of insulin detemir action. Diabetes 54(Suppl 1):A336, 2005.

Hermansen K, Derezinski T, Kim H, Gall MA: Treatment with insulin detemir in combination with oral agents is associated with less risk of hypoglycaemia and less weight gain than NPH insulin at comparable levels of glycaemic improvement in people with type 2 diabetes. Diabetologia 47(Suppl 1):A273, 2004.

Home P, Kurtzhals P: Insulin detemir: from concept to clinical experience. Expert Opin Pharmacother 7:325-343, 2006.

Hordern SVM, Wright JE, Umpleby AM, Shojaee-Moradie F, Amiss J, Russell-Jones DL: Comparison of the effects on glucose and lipid metabolism of equipotent doses of insulin detemir and NPH insulin with a 16-h euglycaemic clamp. Diabetologia 48:420-426, 2005.

Kurtzhals P: Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir. Int J Obes 28(Suppl 2):S23-S28, 2004.

Kurtzhals P, Havelund S, Jonassen I, Markussen J: Effect of fatty acids and selected drugs on the albumin binding of a long-acting, acylated insulin analogue. J Pharm Sci 86:1365-1368, 1997.

Markussen J, Havelund S, Kurtzhals P, Andersen AS, Halstrom J, Hasselager E, Larsen UD, Ribel U, Schaffer L, Vad K, Jonassen I: Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs. Diabetologia 39:281-288, 1996.

Novo Nordisk Inc.: Levemir® (insulin detemir [rDNA origin] injection) [Product Information]. 2005.

Pieber TR, Treichel H-C, Robertson LI, Mordhorst L, Gall M-A: Insulin detemir plus insulin aspart is associated with less risk of major as well as nocturnal hypoglycaemia than insulin glargine plus insulin aspart at comparable levels of glycaemic control in type 1 diabetes. Diabetologia 48(Suppl 1):A92, 2005.

Plank J, Bodenlenz M, Sinner F, Magnes C, Gorzer E, Regittnig W, Endahl LA, Draeger E, Zdravkovic M, Pieber TR: A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 28:1107-1112, 2005.

Raslova K, Bogoev M, Raz I, Leth G, Gall MA, Hancu N: Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract 66:193-201, 2004.

Roberts A, Bayer T, Munksgaard E, Lang H, Standl E: Efficacy and safety of 6-month treatment with insulin detemir in type 1 diabetic patients on a basal-bolus regimen. Diabetes 50(2):A129, 2001.

Russell-Jones D, Kim H, Heller S, Clauson P: Insulin detemir reduces the risk of hypoglycaemia at all levels of HbA1c compared to NPH insulin in the context of basal-bolus therapy for type 1 diabetes. Diabetologia 48(Suppl 1):A92, 2005.

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This article originally posted 11 April, 2006 and appeared in  Issue 307

Past five issues: Diabetes Clinical Mastery Series Issue 199 | Issue 739 | GLP-1 Special Editions July 2014 | Diabetes Clinical Mastery Series Issue 198 | Issue 738 |

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