It’s not just another glargine Levemir®

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

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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.

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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.

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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.

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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.