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Insulin Detemir and Basal Insulin Therapy

David L. Russell-Jones, MD, FRCP
Prqfessor of Diabetes and Endocrinolog3; Postgraduate Medical School, Universi~ c Surrey, Consultant in Charge of the Centre or Endocrinology, Diabetes and Reseamh, Cedar Centre, Royal Surrey CounO' Hospital, GuiIdjord, United Kingdom
With the introduction of insulin detemir (Levemir (~ [Novo Nordisk A/S, Bagsvaerd, Denmark]), a long-acting basal insulin analog, it is an opportune moment to reevaluate the use of basal insulin therapy and consider current treatment strategies, including the use of insulin detemir. This review examines the need for effective treatment options for diabetes and the economic burden of this disease. The importance of achieving glycemic control targets and the role of basal insulin therapy are discussed. Finally, the use of insulin detemir is briefly reviewed wRh a look at its clinical pharmacology, its use in basal insulin therapy', and its cost-effectiveness.

The prevalence of diabetes is rising as a result of the growth of an aging population, unhealthy diets, obesity, and sedentary lifestyles [11. Diabetes is associated with a number of complications that arise despite diagnosis and treatment of the disease. Most patients with diabetes will experience some degree or all of tile common complications that are caused or exacerbated by the condition, including premature macrovascular disease, nephropalhy, retinopathy, and neuropathy [21. A number of trials have shown that the risk of these complications carl be greatly reduced if effective treatment is implemented to reach glycemic control targets [3-5]. Such treatment will often include basal insulin therapy. In this review, the epidemiology and economic costs of diabetes, as well as the importance of achieving glycemic control targets illustrate the need for effective treatment. The use of insulin replacement therapy and the role of basal insulin therapy in diabetes treatment are then discussed. Finally, insulin detemir is discussed, with a summary of its pharmacology, clinical efficacy, and cost-effectiveness.
Diabetes today: an epidemic In 2003, ~194 million people worldwide (5.1%) between file ages of 20 to 79 years were estimated to have diabetes (diagnosed and undiagnosed) [2]. This number has been projected to rise to 333 millkm by 2025 [2]. The highest prevalence of diabetes h-1 2003 was fir North America (23 million [7.9%]) and Europe (48 million [7.8%]) [61. In the United States alone, an estimated 14.6 million children and adults have been diagnosed with diabetes, and it is suspected that an additional 6.2 million remain undiagnosed [71. Tile complications of diabetes are a major cause of morbidity and mortality. In 2002, diabetes contributed to

>224,000 deaths, 12,000 to 24,000 new cases of blindness due to diabetic retinopaihy, 44,400 patients starting treatment for end-stage renal disease, and ~82,000 nontraumatic lower-lfinb amputations fir the Umted States [7]. The total a,mual economic cost of diabetes and related complications m the United States that year was estimated to be $132 billion [7]. Of the $92 billion spent on direct medical expenditures, $24.6 billion was for chronic diabetes-related complications, with cardiovascular disease being tile most costly complication, accounting for $17.6 billion. There is a similar high economic burden m Europe, with estimated direct costs of diabetes care between $43 and $81 billion [6].
Glycemic control targets Glycemic control is fundamental to file management of diabetes. It is usually assessed with fasting plasma glucose (FPG) and pre- or postmeal glucose measurements, as well as by measuring levels of glycosylated hemoglobh-1 (A1C). A1C levels are typically the primary taget for glycemic control, being a marker of the average blood glucose concentraticm over the preceding 2 to 3 months and incorporating both pre- and postprandial glycemia. Several studies m both type 1 and type 2 diabetes have shown that reducing A1C levels to 7% or lower is associated with a significant reduction in tile incidence of microvascular complications (eg, retmopathy and nephropathy) and m the incidence of neuropathy [3-51.

Professor Russell-Jones has received honoria and research grants fl'om bill Lilly and Company, Novo Nordisk Inc., Pharmada Co~oration, and [hkeda Pharmaceutical Company Limited.

Endocrinology and Metabolism Clinics of North America * Supplement 1

Intensive glycemic management resulting in lower A1C levels has also been shown to have a beneficial effect on cardiovascular disease complications in type 1 diabetes [8,91. While there is a lack of unequivocal evidence that intensive glycemic control reduces the risk of death due to macrovascular disease in type 2 diabetes, data suggest that improved glycemic control may be clinically significant at lowering the risk of diabetes-related macrovascular complications [10]. Further to these findings that the morbidity and mortality of diabetes can be reduced by intensive treatment and glycemic control, the American Diabetes Association (AI)A), the American College of Endocrinology/Americ~m Association of Clinical Endocrinologists (ACE/AACE), and the International l)iabetes Federation (II)F) have established goals for glycemic control, including AIC targets of <7.0%, _<6.5%, and <6.5%, respectively (Table) [2,11,12]. Although the ADA recommends an AIC target of <7% for patients in general, its A1C goal for the individual patient is an A1C as close to normal (<6%) as possine without significant hypoglycemia. An A1C level of 7% has been shown to correlate with a mean plasma glucose level of 170 mg/dL over the preceding 2 to 3 months [13]. Similar strict targets have been adopted by the IDF [2] and by many European countries. Recent studies have indicated that such recommended glycemic targets are not achieved by up to 75% of patients with diabetes. An AACE survey of more than 157,000 people with type 2 diabetes found that, during 2003-2004, 67% failed to meet the ACE/ AACE AIC target of _<6.5% [14]. Similarly, a populationbased analysis m Germany and the United Kingdom using data obtained from 6 million patient records showed that the average last recorded A1C level was 8.4% for 3568 adults with type 2 diabetes who were prescribed insulin [15]. Furthermore, despite insulin use, about one third (32.3%) had A1C levels _>9% and ahnost one fifth (18.2%) had A1C levels _>10%. These Table ADA, ACE/AACE, and H)F glycemic goals [12,11,121] ADA A1C Preprandial glucose Postprandial glucose <7.0%~ 90-130 mg/dl. <180 mg/dLb

data show that there is a need to address the gap between recommended glycemic targets and control in the clinical setting.
Insulin replacement therapy

Under normal physiological conditions, insulin is the primary effector in carbohydrate homeostasis. ~I1ae norreal fasting blood glucose concentration (70-110 mg/dL) is associated with very low levels of insulin secretion; however, insulin secretion is rapidly stinurlated in response to increases in blood glucose levels and food intake [16]. In individuals without diabetes, plasma glucose concentrations peak about 60 minutes after the start of a meal, rarely exceed 140 mg/dL, and rettma to preprandial levels within 2 to 3 hours [16]. However, postprandial plasma glucose (PPG) concentrations are higher and more prolonged in individuals with diabetes than in individuals without diabetes. Theoretically, the ideal insulin therapy for patients with diabetes should nfimic normal physiologic insulin release (ie, a low basal level of insulin with an additional boost at mealtimes).
Basal insulin therapy and its role in diabetes treatment

The goal of basal insulin therapy is to deliver a longacting base level of insulin to maintain target blood glucose levels overnight and between meals. For patients with type 1 diabetes, who am unable to produce insulin, basal insulin therapy is a necessity. For patients widl type 2 diabetes, who do not produce sufficient insulin or are insulin resistam, lifestyle changes and oral amidiabetic drugs (OADs) may initially affect sufficient glycemic control. However, type 2 diabetes is a progressive disease and often patients will require additional medication, including insulin, if treatment goals am to be met over time. Both the ADA and ACE/AACE have recently published padlways of therapy to help guide health care providers in d~eir choice of treatment for patients wid~

ACE/AACE _<6.5% _<110mg/dl. _<140mg/dL

IDF <6.5% <110 mg/dL <145 mg/dLb

Abbr<,viatiol~s: AI (2, glycosylated hemoglobin; ACE/AACE, American College of Endocrinology/AmericanAssociation

of Clinical Endocnnologists; ADA, American Diabetes Association; IDK International Diabetes Federation. ~Referenced to a nondiabetic range of 4.0% to 6.0% using a Diabetes Contlx~land Complications Tl{al-based assay, the A1C goal] for patients in general is <7%; however, the AI C goal for the individual patient is as dose to normal (<6%) as possible without significant hypoglycemia. hi_2 fIours after the beginning of the meal. 2-Hour postprandial glucose.

Endocrinology and Metabolism Clinics of North America Supplement 1

type 2 diabetes [17,18]. In the ADA&;urope~m Association for the Study of Diabetes treatment algorithm, initiation of basal insulin (intermediate- or long-acting) is included as an option for patients who have failed to achieve or sustain glycemic goals after lifestyle intervention and maximal tolerated dose of metformin (Fig.) [171. ~lSe guidelines suggest considering insulin as the first option for patients with AI C >8.5% or with symptoms secondary to hyperglycemia. If fl~e alternative options of sulfonylurea or glit~one are chosen and fail to achieve or sustain AIC <7%, then basal insulin is a later option. ~Uae ACE/AACE Road Map for the Prevention and Treatment of ~Ikpe 2 Diabetes is intended to help the medical conmmnity achieve the ACE/AACE Glycemic Control guideline recommendations. In this road map, a combination of therapies, including intermediate- or long-acting insulin preparations, are listed as therapeutic options for targeting FPG and PPG in treatment-naive patients who have an initial A1C between 8% and 10% [18]. For those treatment-naive patients with an A1C of >10%, insulin therapy is recommended: either basal-

bolus insulin including intermediate- or long-acting insulin preparations or premixed insulin analogs. For pretreated patients, basal insulin is included as a concomitant treatment option for patients with an AIC of 6.5% to 8.5% (with basal-bolus therapy as a concomit~mt treatment option for those who have previously received combination therapy). Basal insulin is the only recommended option (long-acting plus rapid-acting insulin or premixed insulin analogs) for pretreated patients with an AIC of >8.5%.
T h e d e v e l o p m e n t o f basal insulin therapy

For m~my decades, ~mimal pancreases were the only source of insulin for clinical use in humans; however, many patients experienced problems with purity and allergic reactions. Recombinant DNA technology enabled the production of synthetic human insulin, which became available m the early 1980s, and insulin analogs have since been produced in an attempt to improve the pharmacodynamic/pharmacokinetic properties of insulin for subcutaneous administration.

Diagnosis ]
Lifestyle Intervention + Netformin

Add Basal Insulin

N o s t effective

Add Sulfonylurea Least expensive

Add Glitazone . No hypoglycemia

Add Basal o r intensify insulin?

Intensive insulin + Netformin +/- Glitazone

Fig. American Diabetes Association and the Em'opean Association for the Study of Diabetes tk~atment algorithm for the metabolic management of type 2 diabetes, with the suggested addition of basal insulin highlighted in bold. (Adapledfiorr~ Nathan DM. Buse JB, l)avidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus Mgorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963-72; with permission.) *Check glycosylated hemoglobin (A1C) every 3 months until <7% and then at least evet3~ 6 months. tlnsulin regimens should be designed taking lifestyle and meal schedule into account. *Although 3 oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense.

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Endocrinology and Metabolism Clinics of North America

* Supplement 1

Several strategies have been employed to produce ~m insulin with a protracted and predictable action profile that would provide basal insulin therapy. ~lhe earliest attempt was to modify insulin absorption by adding neutral protamine Hagedom (NPH) insulin or an excess of zinc (ultralente insulin) to produce a suspension of insulin that would dissolve slowly once iniected. However, careful resuspension of these preparations is required to ensure the correct insulin concentration and to minimize variability between injections [19]. NPH insulin is also characterized by a peak in the pharmacokinetic profile 4 to 6 hours after rejection, followed by a steady decline [20]. ~lhis peak in action and its unpredictability incurs a risk of hypoglycemia ~md limits the tolerable dose [19]. Another strategy, which was used to produce insulin glargine, was to modify the amino acid sequence to shift the isoelectric point so that the insulin analog could be iniected into an acidic medium as a solute, but form a precipitate at a physiological pH level that would slowly dissolve to provide protracted absorption. The most recent strategy, which is used ibr insulin detenfir, has been to acylate a fatty acid to d~e insulin molecule to produce a molecule widl increased self association and reversible albmim>bindmg properties.
Insulin detemir

I~ike any insulin, insulin detemir regulates glucose metabolism through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitaring cellular uptake of glucose into skeletal nmscle and adipose tissue, and by inhibiting the output of glucose from the liver. ~Ilae results of a euglycemic clamp study in healthy volunteers suggested that insulin dctemir, when compared with NPH insulin, has a greater effect on the liver than on peripheral tissues [301. In this study, using equipotent closes of insulin detemir and NPH insulin, insulin dctemir had a greater effect on mean suppression of hepatic glucose rate of appearance (mean difference, 0.24 mg kg -~. minq; CI, 0.09 to 0.39; P < 0.01) and a lesser nonsignificant effect on glucose rote of disposal (mean difference, 0.33 nag. kg q . minq; CI, -0.15 to -0.80) than NPH insulin, suggesting a greater effect on the liver than peripheral tissues. ~I~is differential effect of insulin detemir on hepatic and peripheral glucose metabolism suggests that it may be able to partially restore the normal hepatic/peripheral insulin gradient.

Use ir~patients with type 1 arid 2 diabetes The efficacy and safety of insulin detemir has been studied in more than 6000 patients with type 1 or type 2 diabetes in either basal-bolus or basal-only therapy. Basal-bolus therapy Tile efficacy and safety of insulin detemir in basalbolus therapy administered once or twice daily has been studied in 8 randomized, parallel, controlled trials [31-381, including 2 extension studies [39,401, and in 1 crossover study [411 including more than 3000 patients with type 1 diabetes and in 2 rando~ifized, parallel, controlled trials in 900 patients with type 2 diabetes [42-44]. All except one of these studies, which compared insulin detemir with insulin glargine [34], compared insulin detemir with NPH insulin with either insulin aspart or regular human insulin as bolus lherapy. These studies have shown that once- or twice-daily insulin detemir was as effective as NPH insulin in reducing A1C and FPG. In 2 of the studies, A1C was significantly lower with insulin detemir than wilh NPH insulin [31,32] and, in most of the studies, FPG was reduced to a greater extent with insulin detemir than with NPH insulin [32,33,36,37,41] m patients with type 1 diabetes. Insulin detemir was generally associated wilh a significantly lower within-person day-to-day variation in selfmeasured blood glucose than NPH insulin [31-33, 36-38,41,42,44] and with a lower risk of nocturnal hypoglycemia, which reached statistical significance in many of the studies [31,32,36-39,41,43]. In addition, there was a significant treatment difference with regard to weight outcome in favor of insulin dete~ifir with patients experiencing a small weight loss (of up to 2.1 lb) or gai~fing less or no weight at the end of the study compared with

Insulin detemir is a soluble, long-acting recombinant human insulin analog. It is indicated for once- or twicedaily 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 [21].

Cl#~ical pharmacology Insulin detemir is acylated by a fatty acid that promotes increased self-association and enables reversible albumin binding [22,23]. At the injection site, insulin detemir remains in solution and the molecules combine with each other via the fatty-acid side chains to form hexamers and dihexamers, which then bind to albumin [24]. Self-association and reversible albumin binding are thought to explain lhe long depot residence time of insulin detemir [24]. Once insulin detemir is absorbed into the bloodstream it dissociates into monomers that, again, bind to albumin and slow its distribution l~om the bloodstream to peripheral target tissues [24]. Insulin detemir exhibits a dose-dependent duration of action of up to 24 hours [25,26], with maximum serum concentrations reached between 6 and 8 hours after administration [21]. It has a consistent pharmacokinetic profile across age groups in children, adolescents, and adults with type 1 diabetes [27], as well as in different race/ethnic groups [28,291. (More detailed reformation on the pharmacology of insulin detemir can be found in Kurtzhals in this supplemem.)

Endocrinology and Metabolism Clinics of North America Supplement 1

11

those who received NPH insulin and typically gained weight [31-33,37~-I0,42,441. In comparison with insulin glargine, insulin detemir was as effective at reducing A1C, but was associated with a lower risk of mNor and nocturnal hypoglycemia [341. (More detailed information on the efficacy and safety of insulin detemir can be found in Raskin in this supplement.)

also associated with a reduction in hypoglycemic episodes and a reduction in weight in both groups. ~lllese results confirm clinical trial results that insulin detemir improves glycemic control and reduces the risk of hypoglycemia without weight gain in type 2 diabetes patients.

Cost-e~ectiveness
Ti~e cost-effectiveness of basal insulin, from a US health care perspective, has been assessed using outcome data extracted from randomized controlled trials designed to compare insulin detemir with NPH insulin and insulin glargine [49]. In comparison with NPH insulin, insulin detemir increased quality-adiusted life expect~mcy by 0.698 quality-adjusted life-years (QALYs). Lifetime direct medical costs increased by $10,451 per patient (equating to a cost of $14,974 per QALY gained), although indirect costs were reduced by $4688. In comparison wilh insulin glargine, insulin detemir increased quality-ad}usted life expectancy by 0.063 QALY, with reduced direct (by $2072 per patient) and indirect (by $3103 per patient) medical costs. Insulin detemir was associated with reductions in diabetes-related complications, particularly retinopathy and neuropathy, compared with NPH insulin and, to a lesser extent, compared with insulin glargine. Similarly, in an earlier economic analysis comparing tile cost-effectiveness of insulin detemir versus NPH insulin in a UK setting, insulin detemir was associated with fewer diabetes-related microvascular complications, an increase m quality-adiusted life expectancy of 0.09 year, and increased total lifetime costs per patient of 1707 [50]. Tile cost-effectiveness ratio in this analysis, at 19,285/QALY gained, was considered to be within the range representing an excellent economic value (<35,000/QALY gained).
Summary

Basal-only therapy (add-on to oral anfidiabetic drugs)

Insulin detemir as add-on therapy to OADs has been investigated in 3 randomized, controlled trials in just over 1500 insulin-naive patients with type 2 diabetes, in comparison with NPH insulin [45,46] or insulin glargine [47]. In the first study, comparing twice-daily insulin detemir with NPH insulin, comparable reductions in A1C were achieved in both groups, with 70% of patients achieving A1C levels of-<7% [45]. However, significantly more patients achieved this without hypoglycemia with insulin detemir than with NPH insulin [451. Insulin detemir was also associated with a significantly reduced risk of all hypoglycemia and nocturnal hypoglycemia, and with significantly less weight gain than NPH insulin. In the second study, comparing once-daily morning or evening insulin detemir with once-daily evening NPH insulin, insulin detemir also achieved similar reductions m A1C and significantly reduced risks of nocturnal hypoglycemia, with a significantly reduced risk of 24-hour hypoglycemia and sigifificantly less weight gain for evelfing insulin detelifir versus NPH insulin [46]. In comparison with insulin glargme as add-on therapy to ()ADs, both insulin detemir and insulin glargine were equally effective in optimizing A1C with about 52% of patients achieving an A1C of _<7%, and there was no difference in hypoglycemia risk [47]. Again, significantly less weight gain was observed in patients using insulin detemir compared with those using insulin glargine.

Observational stu@
Tile PREDICTIVE study is a large, multicenter, prospective, observational study assessing tile safety and efficacy of insulin detemir in clinical practice. Results were recently presented for 2 subgroups of patients: OAD-treated insulin-naive type 2 diabetes patients (n = 1321) and type 2 diabetes patients switched from NPH insulin (n = 251) or insulin glargine (n = 260), both with/wilhout ()ADs, to insulin detemir wilh/without ()ADs [48]. In insulin-naive patients, insulin detemir reduced A1C by 1.29%, FPG by 58 mg/dL, and withinsubiect FPG variability by 8.2 mg/dL (calculated as the standard deviation of FPG). There was also a reduction in body weight and in hypoglycemic episodes. In patients switched from NPH insulin and insulin glargine, insulin detemir reduced A1C by 0.60% and 0.59%, respectively, and reduced FPG by 29 mg/dL and 25 mg/dL, respectively. A switch to insulin detemir was

Diabetes and its associated complications represent an increasing health cam burden. Despite many treatment options, patients are still not achieving glycemic targets that have been shown to reduce tile morbidity and mortality associated with this disease. Them is a current drive to more aggressive management in order to achieve more stringent targets and improve outcome. Tiros, there is a need to reassess, on an individual basis, whether patients are receiving optimal treatment. When dosed appropriately, insulin is effective at lowering A1C to reach glycemic ta~ets, which are the accepted gold standard for measuring disease ccmtrol. Recently, insulin analogs with improved pharmacodynamic/ pharmacokmetic properties, such as the long-acting insulin analog, insulin detenfir, have become available. Tile ADA treatment algoridml and ACE/AACE Road Map may help guide healdl care providers in their choice of treammnt and hopefully help more patients achieve their glycemic goals.

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Endocrinology and Metabolism Clinics of North America

* Supplement 1

Insulin detemir is a treatment option for adult and pediatric patients with type I diabetes and adult patients with type 2 diabetes who require basal insulin to coNrol hyperglycemia. It has proven efficacy in reducing AIC and FPG levels in basal-bolus therapy in type 1 and type 2 diabetes and as add-on therapy to OADs in type 2 diabetes. Compared with NPH insulin, insulin detemir has also demonstrated a more consistent blood glucose response, a lower risk of hypoglycemia, and a favorable weight outcome. The improved glycemic control and reduced complication costs associated with insulin detemir also suggest that it is more cost-effective than NPH insulin. Evidence suggests that, in the future, more aggressive and earlier initiation of pharmacologic therapy in type 2 diabetes patients will help reduce the morbidity and mortality, as well as the overall costs, associated with diabetes. Insulin detemir offers an effective treatment option for the management of diabetes. Acknowledgment David L. Russell-Jones, MD, FRCR tha,kks Annette Smith, PhD, of Complete Medical Comnmnications, who provided medical writing support funded by Novo Nordisk Inc. Address correspondence to: David L. Russell-Jones, MD, FRCP, Department of Diabetes and Endocrinology, Royal Surrey County Hospital, Guildford, Surrey GU2 7WG, UK. E-mail: drj@royalsurrey.~flls.uk

References
[1] InternationM Diabetes Federation. Facts and figures. Available at: http://wwwddf.org/home/index.cfm?node=6. Accessed October 19, 2006. [2] International Diabetes Federatkm Clinical Guidelines ['ask Force. Global guideline for type 2 diabetes. Availal)le at: http://www.idf.org/ home/index.cfm?node=1457. Accessed November 28, 2006. [3] I K Prospective 1)ial~etes Study (l KPl)S) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. [4] The Diabetes Control and Complications Trial Research Group. The effect of illtensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. [5] ttellman R, Regan J, Rosen tt. Effect of intensive treatment of diabetes of the risk of death or renal failure in NIDDM and IDDM. Diabetes Care 1997;20:258-64. [6] lnternationM Diabetes Federation. Diabetes Atlas, third edition. www.idl.org Available at: http://www.eatlas.id['.org/media/. Accessed September 9, 2006. [7] American Diabetes Association. Diabetes Statistics. Available at: http://www.diabetes.org/diabetes-statisticsdsp. Accessed September 26, 2006. [8] Nathan I)M, I.achin J, Clea~' R et N. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003 ;348:2294-303.

[9] Nathan DM, ClealT PA, Backlund J-Y, et al. Intensive diabetes treament and cm:diovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643-5% [10] Stratton IM, Adler AI, Nell HA, et al. Association of glycaemia with macl:ovascular and microvascular complications of type 2 diabetes (UKPI)S 35): prospective observatk)nal study. BMJ 2000;321: 405-12. [11] Standards of medical care in diabetes-2006. Diabetes Care 2006;29(Suppl 1):$4-42. [12] American Association of Clinical Endocrinologists. American College of Endo~'inology consensus statement oil guidelines for glycemic control. Aw~ilable at: http://www.aace.com/meetings/consensus/ dcc/pdf/dccwhitepaper.pdl. Accessed September 26, 2006. [13] Rohlfing CL, Wiedmeyer H-M, I,ittle RR, et N. Defining tlle relationship between plasma glucose and HbAlc: analysis of glucose profiles and HbA 1c in the l)ial~etes Control and Compli cati on s Trial. Diabetes Care 2002;25:275-8. [14] State of Diabetes in America TM Report. Available at: http://www. m~ce.com/public/awarcnessNtateofdiabetes/DiabeIes~MnericaReport.pd f. Accessed September 26, 2006. [15] Gough S, Frandsen KB, %ft AD. Faihu'e of insulin monotherapy in patients with type 2 diabetes: a population-based study. 66th Annual Scientific Sessions of the American Diabetes Association; June 9-13, 2006; Washington, DC. [l 6] American I)mbetes Association. Postprandial blood glucose. I)mbetes Care 2001 ;24:775-8. [17] Nathan I)M~ Buse JB, l)avidson MB~ et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006;29:1963-72. [18] ACE/AACE I)ial)etes Road Map ['ask Force. Road map for the prevention and treatment of type 2 diabetes. Available at: http://www. aace.com/meetings/consensus/odimplementation/roadmap.pdf. Accessed September 26, 2006. [19] Kurtzhals P. Engineering predictability and protraction in a basal insulin anMogue: the pharmacology of insulin detemir. Int J Obes 2004;28(Suppl 2):$23-8. [20] Owens I)R, Coates PA, Luzio SD, et al. Pharmacoldnetics of 1251labeled insulin glargine (HOE 901) in healthy men: comparison with NPtt insulin and the influence of different subcutaneous rejection sites. Diabetes Care 2000;23:813-9. [21] Levemir (insulin detemir [rDNA origin] injection ) [prescribing information]. Bagsvaerd, Demnark: Novo Nordisk ~D'S; 2005. [22] Kurtzhals R Havelund S~ Jonassen 1, Markussen J. Effect of fatty adds and selected &'ugs on the albumin binding of a long-acting, acylated insulin anMogue. J Pharm Sci 1997;86:1365-8. [23] Max]alssen J. Havelund S, Kurtzhals R et al. SoluNe, fatty acid acylated insulins bind to albumin and show protracted action in pigs. Diabetologia 1996;39:281-8. [24] Havehmd 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;21:1498-504. [25] Klein O, Lynge J, Endahl L, et al. Albtullin-bolmd 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;9:290-9. [26] Plank J, Bodenlenz M, Sinner E et N. A double-blind, randoiNzed, dose-response study investigating the pharmacodynamic and phaxmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 2005;28:1107-12.

Endocrinology and Metabolism Clinics of North America

Supplement 1

13

[27] Danne T, I,upke K, Walte K, et al. Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 2003 ;26:3087-92. [28] Hompesch M, Tronpin B, tleise T, et aL Time-action profile of insulin detemir and NPtt insulin in patients with Vpe 2 diabetes from different ethnic groups. Diabetes Obes Metab 2006;8:568-7% [29] Jhee SS, Lyness Wll, Rqjas PB, et al. SiiNlaxity of insulin detemir pharmaco~netics, safety, and tolerability profiles in healthy Caucasian and Japanese American subjects. I Clin Pharmacol 2004;44:258-64. [30] Hordern SV, Wright JE, l mpleby AM. C'omparison of the effects on glucose and lipid metabolism of equipotent doses of insulin detemir and NPH insulin with a 16-h euglycaemic clamp. Diabetologia 2005 ;48:420-6. [31] Hermansen K, Fontaine R Kukolja KK, et M. Insulin analogues 6nsulin deteiNr and insulin aspart) versus traditional human insulins (NPtt insulin and regtflax human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia 2004;47:622-9. [32] Ilome P, Bartley R Russell-Jones D, et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randoiNzed clinical trial. Diabetes Care 2004 ;27:1081-7. [33] Pieber TR, Draeger E, Kristensen A, Grill V. Comparison d three multiple iNection regimens for type 1 diabetes: morning plus dinner or bedtime administration of insulin detemir vs. morning plus bedtime NPH insulin. Diabet Med 2005;22:850-7. [34] Pieber TR, Treiche] H-C, Robertson I,I, et al. Insulin detemir plus insulin aspart is associated with less risk of major as well as nocturnal hypoglycae~ma than insulin glargine plus insulin aspaL~ at comparable levels of glycaeiNc control in type 1 diabetes. Diabetologia 2005;48:A92. Abstract. [35] Roberts A, Standl E, Bayer T, et al. Efficacy and safety of 6-month treatmem with insulin detemir in type 1 diabetic patients on a basalbolus regimen. Diabetologia 2001 ;44(Suppl 1 ):A207. Abstract. [36] Robertson KJ, Schoenle E, Gucev Z, et aL Insulin detemir compared with NPH insulin in children and adolescents with type I diabetes. Diabet Med 2007;24:27-34. [37] Russdl-Jones D, Simpson R, Hylleberg B, eta]. Effects of QD insulin detemir or neutrM protamine Hagedorn on blood glucose control in patients with type I diabetes mellitus using a basal-bolus regimen. Clin Ther 2004;26:724-36. [38] \~gue R Selam J-L, Skeie S, et aL Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglyceiNa than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeM insulin aspart. Diabetes Care 2003 ;26:590~5. [39] De Leeuw I, Vague R Selam J-L, et aL Insulin deteiNr used in basalbolus therapy in people with Vpe 1 diabetes is associated with a lower

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

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