518420
research-article2013
AOPXXX10.1177/1060028013518420Annals of PharmacotherapyWallace et al
Review Article
Comparing Dosing of Basal Insulin Analogues Detemir and Glargine: Is It Really Unit-Per-Unit and Dose-Per-Dose?
Annals of Pharmacotherapy 2014, Vol. 48(3) 361–368 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013518420 aop.sagepub.com
Juliet P. Wallace, PharmD1, Jessica L. Wallace, PharmD, BCPS1,2, and M. Shawn McFarland, PharmD, BCPS, BCACP, BC-ADM1,3
Abstract Objective: To review the available evidence regarding dosing conversion between glargine and detemir in an effort to assist clinicians in performing dosing conversion. Data Sources: A MEDLINE literature search was performed using the search terms glargine and detemir for articles published through August 2013. Study Selection and Data Extraction: All English-language clinical trials were reviewed for inclusion of dosing and/or pharmacokinetic data. Data Synthesis: A total of 7 large (n ≥ 258) randomized controlled trials (RCTs) comparing glargine and detemir in patients with type 1 and 2 diabetes had dosing equivalency data available. In these 7 RCTs, on average, a 38% higher detemir dose was required (range = 8.0%-77.2%) to achieve glucose control comparable to that achieved with glargine. A 24-hour isoglycemic clamp study conducted in 11 patients with type 1 diabetes demonstrated that the duration of action of detemir is dose dependent, with increasing doses of detemir resulting in increased duration of action of detemir. Pharmacokinetic studies conducted in patients with type 2 diabetes are conflicting, although the majority of evidence suggests that glargine provides a longer duration of glycemic control as compared with detemir. Conclusions: When performing conversion between glargine and detemir, prescribers should be aware that higher doses of detemir as compared with glargine may be necessary to achieve the same glycemic control. Additionally, twice-daily injections of detemir should be considered in clinical situations in which glucose control appears to decline after 12 hours, especially with doses ≤0.4 units/kg/d in patients with type 1 diabetes. Keywords dosing, insulin, diabetes, adult medicine, ambulatory care, clinical decision making, clinical pharmacy
Introduction Basal insulin therapy is required for the treatment of type 1 diabetes and is often necessary following progression of type 2 diabetes in an effort to maintain optimal glycemic control. Basal insulin therapy can be provided by neutral protamine Hagedorn (NPH) human insulin or newer, longacting insulin analogues. NPH insulin has a duration of action of 8 to 12 hours, which necessitates twice-daily injections for 24-hour basal coverage. NPH is supplied as a suspension, and if inadequately resuspended prior to injection, it will provide inconsistent glycemic control.1 NPH insulin is associated with a higher risk of nocturnal and severe hypoglycemia because of its peak effect occurring approximately 4 to 6 hours after injection, whereas longacting insulin analogues provide a flatter, more physiological basal insulin replacement and improved glycemic profiles.2 There are currently 2 long-acting basal insulin
analogues available in the United States—insulin glargine (Lantus; sanofi aventis, Bridgewater, NJ) and insulin detemir (Levemir; Novo Nordisk, Princeton, NJ)—which received initial Food and Drug Administration approval in 2000 and 2005, respectively.3,4 Clinical trials have established that there is no clinically relevant difference in efficacy or safety between glargine and detemir, but dosing equivalency and frequency remains controversial.5 Because of transitions of care and changing hospital and insurance formularies, patients often have to be switched 1
Tennessee Valley Healthcare System, Nashville, TN, USA Lipscomb University College of Pharmacy, Nashville, TN, USA 3 University of Tennessee College of Pharmacy, Memphis, TN, USA 2
Corresponding Author: Jessica L. Wallace, PharmD, BCPS, Lipscomb University College of Pharmacy, One University Park Drive, Nashville, TN 37204, USA. Email: [email protected]
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Table 1. Studies Comparing Glargine and Detemir Dosage.
Study
Design 6
Pieber et al Hollander et al16 Kabadi10 Rosenstock et al11 Borah et al18 Raskin et al17 Heller et al7 Swinnen et al12 Verges et al22 Jakobsen et al21 Meneghini et al13 Bryant et al9
RCT RCT
Population n = 320; Type I DM n = 319; Type II DM
Detemir Glargine Detemir Dose Dose (units/ dose Duration (units/kg/d) kg/d) (units/d)
Percentage Glargine Change dose (Glargine to (units/d) Detemir)a P Valuea
26 Weeks 52 Weeks
0.47 0.82
0.35 0.59
— —
— —
34.3 39.0
— —
Obs, R n = 24; Type I DM RCT n = 582; Insulin naïve, type II DM Obs, R n = 306; Type I and II DM RCT n = 385; Type II DM on basal-bolus RCT n=443; Type I DM RCT, C n = 973; Insulin naïve type II DM Obs, P n = 2745; Insulin naïve type II DM Obs, R n = 536; Type II DM
6 Months 52 Weeks
— 0.78
— 0.44
46.0 —
35.0 —
31.4 77.2
30 minutes, within the 32-hour monitoring period. The total glucose infusion rate area under the curve was 42% higher with glargine versus detemir (P < .05), suggesting that glargine provides better glucose control for up to 32 hours, although conclusions regarding
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duration of action cannot be made based on these data alone. Kato et al28 evaluated glucose profiles of patients with both type 1 and 2 diabetes in a crossover comparison of glargine versus detemir injected once daily before dinner. In patients with both type 1 and 2 diabetes, postdinner glucose values were significantly higher with detemir (P < .01 and P < .05 for type 1 diabetes and type 2 diabetes groups, respectively). Insulin replacement with glargine also resulted in significantly lower bedtime glucose levels in patients with type 1 diabetes and significantly lower predinner glucose levels in patients with type 2 diabetes (P < .05 for both).
Discussion There is significant heterogeneity among the studies discussed because the patient populations have varied dramatically with respect to glycemic control and other characteristics. Protocols for insulin dosing also vary significantly among the trials conducted because previously there has been no clear consensus on when once- versus twice-daily detemir dosing is required. This may have introduced bias in trials in which the protocol required once- or twice-daily dosing or allowed for differences in the frequency of dosing of detemir versus glargine. Basal insulin dosing may have also been affected by background bolus insulin and noninsulin antidiabetic therapies. Because of the diversity of these studies, it would be difficult to appropriately combine the available data into metaanalyses. However, there is a definite trend toward increased dosing with detemir as compared with glargine. Of the 7 large RCTs (n ≥ 258) discussed, on average, a 38% higher detemir dose was required (range = 8.0%-77.2%) to achieve glucose control comparable to that achieved with glargine in patients with both type 1 and 2 diabetes. The studies discussed are not without limitations. Dosing conversion has not been a major focus of the trials conducted because the majority of trials were noninferiority studies with safety and efficacy end points. Very few studies have aimed to primarily compare dosing conversion. Additionally, because glargine has been available on the market longer than detemir, very little evidence regarding conversion from detemir to glargine is available. Potential author bias is also a major issue with these studies because the large majority of trials comparing glargine and detemir were sponsored, funded, designed, and/or conducted by Novo Nordisk, the manufacturers of Levemir, and some have been criticized for their trial design possibly favoring detemir. The majority of the published studies were open label in design, with neither blinded participants nor study personnel, and patient compliance may have been biased toward the detemir arm in the many Novo Nordisk–funded studies in which detemir was supplied in a pen-injector device and glargine was supplied as vials and syringes.
Some of the trials discussed in this review seem to suggest that twice-daily dosing may be necessary with higher doses of detemir. This may have been a result of the required dose exceeding the maximum dose held by the syringe or delivered by the pen device, which is 60 units with the Levemir FlexPen.3 Several of the studies discussed found that higher, twice-daily dosing of detemir was not associated with corresponding improved glycemic control.7,8,16 Pharmacokinetic studies have shown that the duration of action of detemir is dose dependent, yet shorter, with lower unit-per-kg doses as opposed to higher doses, and may not adequately provide 24-hour basal coverage, especially with doses ≤0.4 units/kg/d in patients with type 1 diabetes. Differences in formulation may explain why detemir and glargine differ with respect to dose and duration of action. As compared with glargine, detemir has a lower affinity for the human insulin receptor (18%) and is formulated at a molar concentration that is 4 times higher to compensate for this lower affinity.29 Additionally, detemir reversibly binds to albumin and is soluble at neutral pH, which accounts for its extended duration of action, whereas, glargine depends on precipitation and subsequent dissolution for systemic absorption and sustained action.30
Summary Despite prescribing information for Levemir indicating that conversion from glargine can be done on a unit-per-unit basis, health care providers performing conversion between glargine and detemir should be aware that higher doses of detemir as compared with glargine may be necessary to achieve the same glycemic control. When converting from glargine to detemir, a conservative initial increase in dosage could potentially be considered, specifically in patients being converted to twicedaily detemir, based on the current available evidence. Conversely, there is little evidence regarding conversion from detemir to glargine. Theoretically, however, an empirical dosage reduction could be considered in order to minimize the risk of hypoglycemia resulting from nonequivalent unit-per-unit dosing. Additionally, twice-daily injections of detemir should be considered in clinical situations in which glucose control appears to decline after 12 hours, especially with doses ≤0.4 units/kg/d in patients with type 1 diabetes. To further evaluate dosing conversion between glargine and detemir, further RCTs of appropriate duration, limited potential bias, and strengthened internal and external validity are needed. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Wallace et al Authors’ Note This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System.
References 1. Jehle PM, Micheler C, Jehle DR, Breitig D, Boehm BO. Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens. Lancet. 1999;354:1604-1607. doi:10.1016/ S0140-6736(98)12459-5. 2. Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes: a meta-analysis. Diabetes Obes Metab. 2009;11:372-378. doi:10.1111/j.1463-1326.2008.00976.x. 3. Levemir (insulin detemir) [prescribing information]. Princeton, NJ: Novo Nordisk Inc; 2005. 4. Lantus (insulin glargine) [prescribing information]. Bridgewater, NJ: sanofi-aventis; 2007. 5. Swinnen SG, Simon AC, Holleman F, Hoekstra JB, Devries JH. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011;(7):CD006383. doi:10.1002/14651858.CD006383.pub2. 6. Pieber TR, Treichel HC, Hompesch B, et al. Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy. Diabet Med. 2007;24:635-642. doi:10.1111/j.1464-5491.2007.02113.x. 7. Heller S, Koenen C, Bode B. Comparison of insulin detemir and insulin glargine in a basal-bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: a 52-week, multinational, randomized, open-label, parallel-group, treat-to-target noninferiority trial. Clin Ther. 2009;31:2086-2097. doi:10.1016/j.clinthera.2009.10.006. 8. Le Floch JP, Levy M, Mosnier-Pudar H, et al. Comparison of once- versus twice-daily administration of insulin detemir, used with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes: assessment of detemir administration in a progressive treat-to-target trial (ADAPT). Diabetes Care. 2009;32:32-37. doi:10.2337/dc08-0332. 9. Bryant GA, McDanel DL, Horner KE, Farris KB, Newkirk EN. Evaluation of dosing and clinical outcomes in patients undergoing conversion of insulin glargine to insulin detemir. Pharmacotherapy. 2013;33:56-62. doi:10.1002/phar.1168. 10. Kabadi UM. Deleterious outcomes after abrupt transition from insulin glargine to insulin detemir in patients with type 1 diabetes mellitus. Clin Drug Investig. 2008;28:697-701. 11. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add- on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008;51:408-416. doi:10.1007/s00125-007-0911-x. 12. Swinnen SG, Dain MP, Aronson R, et al. A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs. Diabetes Care. 2010;33:1176-1178. doi:10.2337/dc09-2294. 13. Meneghini L, Kesavadev J, Demissie M, Nazeri A, Hollander P. Once-daily initiation of basal insulin as add-on to
metformin: a 26-week, randomized, treat-to-target trial comparing insulin detemir with insulin glargine in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15:729-736. doi:10.1111/dom.12083. 14. King AB. Once-daily insulin detemir is comparable to oncedaily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study. Diabetes Obes Metab. 2009;11:69-71. doi:10.1111/j.1463-1326.2008.01014.x. 15. King AB. No higher dose requirements with insulin detemir than glargine in type 2 diabetes: a crossover, double-blind, and randomized study using continuous glucose monitoring. J Diabetes Sci Technol. 2010;4:151-154. 16. Hollander P, Cooper J, Bregnhoj 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;30:19761987. doi:10.1016/j.clinthera.2008.11.001. 17. Raskin P, Gylvin T, Weng W, Chaykin L. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev. 2009;25:542-548. doi:10.1002/dmrr.989. 18. Borah BJ, Darkow T, Bouchard J, Aagren M, Forma F, Alemayehu B. A comparison of insulin use, glycemic control, and health care costs with insulin detemir and insulin glargine in insulin-naive patients with type 2 diabetes. Clin Ther. 2009;31:623-631. doi:10.1016/j. clinthera.2009.03.005. 19. Heintjes EM, Thomsen TL, Penning-van Beest FJ, Christensen TE, Herings RM. Glycemic control and long-acting insulin analog utilization in patients with type 2 diabetes. Adv Ther. 2010;27:211-222. doi:10.1007/s12325-010-0020-y. 20. McAdam-Marx C, Yu J, Bouchard J, Aagren M, Brixner DI. Comparison of daily insulin dose and other antidiabetic medications usage for type 2 diabetes patients treated with an analog basal insulin. Curr Med Res Opin. 2010;26:191-201. doi:10.1185/03007990903432470. 21. Jakobsen M, Dalsgaard M, Hormann M, Moller DV. Insulin analogues dosing and costs - comparing real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients. BMC Endocr Disord. 2012;12:21. doi:10.1186/14726823-12-21. 22. Verges B, Brun JM, Tawil C, Alexandre B, Kerlan V. Strategies for insulin initiation: insights from the French LIGHT observational study. Diabetes Metab Res Rev. 2012;28:97-105. doi:10.1002/dmrr.1288. 23. Dornhorst A, Luddeke HJ, Koenen C, et al. Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow- up data from PREDICTIVE. Diabetes Obes Metab. 2008;10:75-81. doi:10.1111/j.1463-1326.2007.00816.x. 24. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005;28:1107-1112.
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25. Porcellati F, Rossetti P, Busciantella NR, et al. Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double- blind, randomized, crossover study. Diabetes Care. 2007;30:2447-2452. doi:10.2337/dc07-0002. 26. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9:290-299. doi:10.1111/j.1463-1326.2006.00685.x. 27. Lucidi P, Porcellati F, Rossetti P, et al. Pharmacokinetics and pharmacodynamics of therapeutic doses of basal insulins NPH, glargine, and detemir after 1 week of daily administration at bedtime in type 2 diabetic subjects: a randomized
cross-over study. Diabetes Care. 2011;34:1312-1314. doi:10.2337/dc10-1911. 28. Kato T, Tokubuchi I, Muraishi K, et al. Distinct pharmacodynamics of insulin glargine and insulin detemir: crossover comparison in Type 1 and Type 2 diabetic patients on basalbolus regimen. Diabetes Res Clin Pract. 2010;90:e64-e66. doi:10.1016/j.diabres.2010.08.011. 29. Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49:999-1005. 30. Havelund S, Plum A, Ribel U, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res. 2004;21:1498-1504.
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research-article2013
AOPXXX10.1177/1060028013518420Annals of PharmacotherapyWallace et al
Review Article
Comparing Dosing of Basal Insulin Analogues Detemir and Glargine: Is It Really Unit-Per-Unit and Dose-Per-Dose?
Annals of Pharmacotherapy 2014, Vol. 48(3) 361–368 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013518420 aop.sagepub.com
Juliet P. Wallace, PharmD1, Jessica L. Wallace, PharmD, BCPS1,2, and M. Shawn McFarland, PharmD, BCPS, BCACP, BC-ADM1,3
Abstract Objective: To review the available evidence regarding dosing conversion between glargine and detemir in an effort to assist clinicians in performing dosing conversion. Data Sources: A MEDLINE literature search was performed using the search terms glargine and detemir for articles published through August 2013. Study Selection and Data Extraction: All English-language clinical trials were reviewed for inclusion of dosing and/or pharmacokinetic data. Data Synthesis: A total of 7 large (n ≥ 258) randomized controlled trials (RCTs) comparing glargine and detemir in patients with type 1 and 2 diabetes had dosing equivalency data available. In these 7 RCTs, on average, a 38% higher detemir dose was required (range = 8.0%-77.2%) to achieve glucose control comparable to that achieved with glargine. A 24-hour isoglycemic clamp study conducted in 11 patients with type 1 diabetes demonstrated that the duration of action of detemir is dose dependent, with increasing doses of detemir resulting in increased duration of action of detemir. Pharmacokinetic studies conducted in patients with type 2 diabetes are conflicting, although the majority of evidence suggests that glargine provides a longer duration of glycemic control as compared with detemir. Conclusions: When performing conversion between glargine and detemir, prescribers should be aware that higher doses of detemir as compared with glargine may be necessary to achieve the same glycemic control. Additionally, twice-daily injections of detemir should be considered in clinical situations in which glucose control appears to decline after 12 hours, especially with doses ≤0.4 units/kg/d in patients with type 1 diabetes. Keywords dosing, insulin, diabetes, adult medicine, ambulatory care, clinical decision making, clinical pharmacy
Introduction Basal insulin therapy is required for the treatment of type 1 diabetes and is often necessary following progression of type 2 diabetes in an effort to maintain optimal glycemic control. Basal insulin therapy can be provided by neutral protamine Hagedorn (NPH) human insulin or newer, longacting insulin analogues. NPH insulin has a duration of action of 8 to 12 hours, which necessitates twice-daily injections for 24-hour basal coverage. NPH is supplied as a suspension, and if inadequately resuspended prior to injection, it will provide inconsistent glycemic control.1 NPH insulin is associated with a higher risk of nocturnal and severe hypoglycemia because of its peak effect occurring approximately 4 to 6 hours after injection, whereas longacting insulin analogues provide a flatter, more physiological basal insulin replacement and improved glycemic profiles.2 There are currently 2 long-acting basal insulin
analogues available in the United States—insulin glargine (Lantus; sanofi aventis, Bridgewater, NJ) and insulin detemir (Levemir; Novo Nordisk, Princeton, NJ)—which received initial Food and Drug Administration approval in 2000 and 2005, respectively.3,4 Clinical trials have established that there is no clinically relevant difference in efficacy or safety between glargine and detemir, but dosing equivalency and frequency remains controversial.5 Because of transitions of care and changing hospital and insurance formularies, patients often have to be switched 1
Tennessee Valley Healthcare System, Nashville, TN, USA Lipscomb University College of Pharmacy, Nashville, TN, USA 3 University of Tennessee College of Pharmacy, Memphis, TN, USA 2
Corresponding Author: Jessica L. Wallace, PharmD, BCPS, Lipscomb University College of Pharmacy, One University Park Drive, Nashville, TN 37204, USA. Email: [email protected]
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Table 1. Studies Comparing Glargine and Detemir Dosage.
Study
Design 6
Pieber et al Hollander et al16 Kabadi10 Rosenstock et al11 Borah et al18 Raskin et al17 Heller et al7 Swinnen et al12 Verges et al22 Jakobsen et al21 Meneghini et al13 Bryant et al9
RCT RCT
Population n = 320; Type I DM n = 319; Type II DM
Detemir Glargine Detemir Dose Dose (units/ dose Duration (units/kg/d) kg/d) (units/d)
Percentage Glargine Change dose (Glargine to (units/d) Detemir)a P Valuea
26 Weeks 52 Weeks
0.47 0.82
0.35 0.59
— —
— —
34.3 39.0
— —
Obs, R n = 24; Type I DM RCT n = 582; Insulin naïve, type II DM Obs, R n = 306; Type I and II DM RCT n = 385; Type II DM on basal-bolus RCT n=443; Type I DM RCT, C n = 973; Insulin naïve type II DM Obs, P n = 2745; Insulin naïve type II DM Obs, R n = 536; Type II DM
6 Months 52 Weeks
— 0.78
— 0.44
46.0 —
35.0 —
31.4 77.2
30 minutes, within the 32-hour monitoring period. The total glucose infusion rate area under the curve was 42% higher with glargine versus detemir (P < .05), suggesting that glargine provides better glucose control for up to 32 hours, although conclusions regarding
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duration of action cannot be made based on these data alone. Kato et al28 evaluated glucose profiles of patients with both type 1 and 2 diabetes in a crossover comparison of glargine versus detemir injected once daily before dinner. In patients with both type 1 and 2 diabetes, postdinner glucose values were significantly higher with detemir (P < .01 and P < .05 for type 1 diabetes and type 2 diabetes groups, respectively). Insulin replacement with glargine also resulted in significantly lower bedtime glucose levels in patients with type 1 diabetes and significantly lower predinner glucose levels in patients with type 2 diabetes (P < .05 for both).
Discussion There is significant heterogeneity among the studies discussed because the patient populations have varied dramatically with respect to glycemic control and other characteristics. Protocols for insulin dosing also vary significantly among the trials conducted because previously there has been no clear consensus on when once- versus twice-daily detemir dosing is required. This may have introduced bias in trials in which the protocol required once- or twice-daily dosing or allowed for differences in the frequency of dosing of detemir versus glargine. Basal insulin dosing may have also been affected by background bolus insulin and noninsulin antidiabetic therapies. Because of the diversity of these studies, it would be difficult to appropriately combine the available data into metaanalyses. However, there is a definite trend toward increased dosing with detemir as compared with glargine. Of the 7 large RCTs (n ≥ 258) discussed, on average, a 38% higher detemir dose was required (range = 8.0%-77.2%) to achieve glucose control comparable to that achieved with glargine in patients with both type 1 and 2 diabetes. The studies discussed are not without limitations. Dosing conversion has not been a major focus of the trials conducted because the majority of trials were noninferiority studies with safety and efficacy end points. Very few studies have aimed to primarily compare dosing conversion. Additionally, because glargine has been available on the market longer than detemir, very little evidence regarding conversion from detemir to glargine is available. Potential author bias is also a major issue with these studies because the large majority of trials comparing glargine and detemir were sponsored, funded, designed, and/or conducted by Novo Nordisk, the manufacturers of Levemir, and some have been criticized for their trial design possibly favoring detemir. The majority of the published studies were open label in design, with neither blinded participants nor study personnel, and patient compliance may have been biased toward the detemir arm in the many Novo Nordisk–funded studies in which detemir was supplied in a pen-injector device and glargine was supplied as vials and syringes.
Some of the trials discussed in this review seem to suggest that twice-daily dosing may be necessary with higher doses of detemir. This may have been a result of the required dose exceeding the maximum dose held by the syringe or delivered by the pen device, which is 60 units with the Levemir FlexPen.3 Several of the studies discussed found that higher, twice-daily dosing of detemir was not associated with corresponding improved glycemic control.7,8,16 Pharmacokinetic studies have shown that the duration of action of detemir is dose dependent, yet shorter, with lower unit-per-kg doses as opposed to higher doses, and may not adequately provide 24-hour basal coverage, especially with doses ≤0.4 units/kg/d in patients with type 1 diabetes. Differences in formulation may explain why detemir and glargine differ with respect to dose and duration of action. As compared with glargine, detemir has a lower affinity for the human insulin receptor (18%) and is formulated at a molar concentration that is 4 times higher to compensate for this lower affinity.29 Additionally, detemir reversibly binds to albumin and is soluble at neutral pH, which accounts for its extended duration of action, whereas, glargine depends on precipitation and subsequent dissolution for systemic absorption and sustained action.30
Summary Despite prescribing information for Levemir indicating that conversion from glargine can be done on a unit-per-unit basis, health care providers performing conversion between glargine and detemir should be aware that higher doses of detemir as compared with glargine may be necessary to achieve the same glycemic control. When converting from glargine to detemir, a conservative initial increase in dosage could potentially be considered, specifically in patients being converted to twicedaily detemir, based on the current available evidence. Conversely, there is little evidence regarding conversion from detemir to glargine. Theoretically, however, an empirical dosage reduction could be considered in order to minimize the risk of hypoglycemia resulting from nonequivalent unit-per-unit dosing. Additionally, twice-daily injections of detemir should be considered in clinical situations in which glucose control appears to decline after 12 hours, especially with doses ≤0.4 units/kg/d in patients with type 1 diabetes. To further evaluate dosing conversion between glargine and detemir, further RCTs of appropriate duration, limited potential bias, and strengthened internal and external validity are needed. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Wallace et al Authors’ Note This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System.
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