- Email: [email protected]
Efficacy and Safety of Insulin Detemir
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Efficacy and Safety of Insulin Detemir Philip Raskin, MD Professor of Internal Medicine-Endocriaolog3; Clifton and Betsy Robinson Chair in Biomedical Research, U~Tiversity qf 7~xas Southwestern Medical Center at Dallas, Dallas, 7>xas
In the treatment of patients with diabetes, the tear of hypoglycemia is a major barrier to initiating, maintaining, and/or intensifying insulin therapy. Insulin detemir (Levemir ® [Novo Nordisk A/S, Bagsvaerd, Denmark]) is a novel, long-acting, basal insulin analog associated with a reduced risk of hypoglycemia that is available to improve glycemic control. This article discusses clinical trial data on the safety and efficacy of insulin detemir in patients with type I and type 2 diabetes. In addRhm, results from the German cohort of the Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation (PREDICTIVE TM)study, a large, multinational observational study examining the clinical effectivehess and safety of insulin detemir, are reviewed. Finally, an evaluation of these data serves to show how the highly predictable action of insulin detemir translates into effective glycemic control with a lower incidence of hypoglycemia. Diabetes mellitus is a chronic disease that is characterized by hype~lycemia. Patients with type 1 diabetes exhibit al absolute or severe deficiency m insulin secretion aid require the ad~mfistration of exogenous insulin for survival. Type 2 diabetes is characterized by a combination of insulin deficiency and insulin resistance, and is often i,fitially controlled by dietau modification, an increase in physical activity, and oral antihyperglycemic agents. However, those patients who cannot maintain adequate glycemic control often require insulin therapy as file disease progresses. Intensive therapy to normalize blood glucose levels has been shown to substantially reduce the microvascular complicaticms associated with type 1 ~mdtype 2 diabems [1-31, Subsequently, individual targets for glycemic control have been set by both tile American Diabetes Association (ADA) arid the American Association of Clhfical Endocrinologists (AACE) [4,5]. Tile ADA currently recommends a target glycosylated hemoglobin (A1C) of <7% for patients in general, but reco,lunends that eadl patient achieve an A1C as close m normal (6%) as possible. Tile AACE suggests aiming ibr a target of 6.5% or lower. Tile ADA also proposes a target range for l:astmg plasma glucose (FPG) levels between 70 and 130 ng/dL, whereas the AACE reconnnends levels below 110 ~IN/dL. Tile m~iority of patients with diabetes are not achieving adequate glycemic control [6] and it is thought that the risk of hypoglycemia is the primary obstacle [6-8]. Indeed, among both patiems with diabetes arid health care profes-
sionals, hypoglycemia is one of tile most feared consequences of intensive insulin therapy [9]. Results from tile Diabetes Control and Complications Trial show that, as patiems approach target A1C levels, there is a 26% increase in the risk of hypoglycemia for each 1% reduction in A1C [10]. Tile inci&nce of hypoglycemia has been correlated with variability m blood glucose response to insulin [111. In addition, variability in blood glucose has been established as an independent risk factor for mortality [12]. Recently, the acylation of fatty acids to the insulin molecule has cuhninated m the clinical availability of insulin detemir. Insulin detemir is a neutral, soluble, long-acting insulin analog for*ned by the removal of tile amino acid threonine at file B30 locus and the acylation of a 14-carbon fatty acid (myristic acid) to lysine at locus B29 [131. Tile acylation of a fatty acid to the insulin molecule stabilizes self-association into dihexamers and permits reversible insulin-albmifin binding that, together, am thought to mediate its slow absorption from the subcutaneous depot and prolong its duration of action [13]. Tile unique albumin binding properties of insulin dete,ifir contribute to a significant reduction in intrapatient variability of pharmacokinetic and pharmacodynamic profles compared with other basal insulin preparations [13[, which is discussed further by Kurtzhals hi this supplement. Dr. Raskin is on the Advisory Board of Novo Nol'disk and has received a grant from sanofi-aventis.
22
Endocrinology and Metabolism Clinics of North America * Supplement 1
This article reviews the efficacy and safety of insulin detemir in patients with type I and type 2 diabetes, and examines the clinical benefits of its unique pharmacodynamic profile. Efficacy and safety of insulin detemir in patients with type 1 diabetes
~II~e efficacy and safety of insulin detemir have been examined in more than 3500 patients wifl~ type 1 diabetes in 11 trials (10 randomized, parallel, controlled trials and 1 crossover study), the results of which are discussed here. In general, the improvements in glycemic control observed with insulin detemir were accompanied with a reduced or similar risk of hypoglycemia in all comparative trials. P.i~ticacy in pafients wifh O'Pe I diabetes Overall, the level of metabolic control achieved with insulin detemir, as assessed by A1C levels, is comparable to that achieved with neutral protamine Hagedom (NPH) insulin (Table 1) and insulin glargine [14-21]. In 2 of tile studies, A1C levels were significantly lower m patients receiving insulin detemir compared with those receiving NPH insulin [22,23]. Insulin detemir has been shown to improve fasting glucose levels and effect more consistent blood glucose profiles than NPH insulin. In a 16-week dose-timing study, FPG levels were lower m patients receiving insulin detemir than in dlose receiving NPH insulin, irrespective of dosing regimen employed (P = 0.006) [171. At the end of another 16-week study, FPG was lower m patients randomized to receive insulin detemir every 12 hours (-27.0 mg/dL vs NPH [95% CI, -45.2 to -8.61; P = 0.004) or m tile morning and at bedtime (-41.4 mg/dL [-59.8 to -23.2]; CI, P < 0.001); compared with NPH insulin administered before breakfast and at bedtime [23]. Further, insulin detemir, with regular human insulin at mealtimes, led to reductions m bodl FPG (-29.0 mg/dL, P = 0.001) and the 9-point self-measured plasma glucose profiles, compared with NPH insulin in combination with regular human insulin (P = 0.006) [19]. Basal-bolus insulin therapy widl all all-analog regimen led to improvements m 8-point plasma glucose profiles and postprandial glucose excursions, compared widl a human insulin-based regimen [22]. Moreover, an analysis of die 10-point glucose profile by Pieber et al [17], demonstrated that nocturnal glucose levels were lower m patients receiving insulin detemir than in those treated widl NPH insulin (P = 0.043). In addition, the results from continuous glucose molfitoring co~Nrmed flatter and more consistent nocturnal glucose levels in patients treated with insulin detemir [17]. To date, only 1 stu@ has directly compared die effects of insulin detemir and insulin gla~ine m patients with type 1 diabetes [181. The results from this 26-week study
suggest fl~at insulin detemir is as effective as insulin glargine in improving AIC and produces a similar 9-point plasma glucose profile [181. In summary, these studies demonstrate that insulin detemir is as effective as NPH insulin and insulin glargine in establishing and maintaining glycemic control. Sajea, in patienf~~wi#z f3~)e l diabefes A number of studies in patients with type 1 diabetes have demonstrated that treatment with insulin detemir results in a low risk of hypoglycemia, particularly, nocturnal hypoglycemia [ 15,16,19,21-23] (Fig. 1), and reduced intrapatient variability in FPG [16,17,19,21-23] (Fig. 2) compared with NPH insulin. Interestingly, it has been reported recently that the reduction in intrapatient FPG variability is a major contributor to tile reduced risk of nocturnal hypoglycemia observed with insulin detemir relative to NPH insulin [11]. A recent pooled analysis i?om 4 multicenter, randomized, clinical trials involving 1180 patients receiving insulin detemir and 810 patients receiving NPH illustrated that tile relative risk of hypoglycemia was 22% lower in patients randomized to insulin detemir (P < 0.001) [24,25]. Furfllermore, compared with NPH, insulin detemir was associated with a lower risk of hypoglycemia at all A1C levels, which suggests that insulin detenfir may allow more patients to achieve effective glycemic control with a lower associated risk of hypoglycemia [24,251. In a 6-month clinical trial comparing insulin detemir with NPH insulin, the significant reduction in intrapadent variability (P < 0.001) observed m patients receiving insulin detemir was accompanied wifll a 22% reduction m tile overall risk of hypoglycemia (P < 0.05) and a 34% reduction in the risk of nocturnal hypoglycemia (P < 0.005) relative to NPH insulin [21]. There were fewer hypoglycemic events in a 6-month extension of the study, and the risk of nocturnal hypoglycemia was 32% lower (P = 0.02) with insulin detemir than with NPH insulin [151. In addition, insulin detemir significantly reduced intrapatient variation m FPG values (P < 0.001) and reduced the risk of nocturnal hypoglycemia (-26%; P = 0.003) compared with NPH insulin when used in basal-bolus therapy with mealtime human insulin for 6 mondls [19]. Tile only study to report tile risk of hypoglycemia as its primary end point is a crossover study consisting of two 16-week treatment periods with either insulin detemir or NPH insulin in combination widl premeal insulin aspart [16]. In this study, a 50% reduction m nocturnal hypoglycemia (P < 0.0001) and an 18% reduction in overall hypoglycemia (P = 0.001) was observed with insulin detemir relative to NPH insulin and was accompanied by a reduction m mtrapatient variation in FPG (P < 0.001) [16].
Endocrinology and Metabolism Clinics of North America
When compared with insulin glargine, insulin detemir significantly reduced intrapatient variability in predinner plasma glucose (P < 0.05) and reduced the risk of both major (-72%) and nocturnal (-32%) hypoglycemia (P < 0.05) [181.
® Supplement 1
23
Efficacy and safeO" in children and adolescents with O'pe 1 diabetes One study has examined the efficacy and safety of insulin detemir in children and adolescents [26]. Robertson et al [26] presented the results of a 26-week,
~[hble 1 Efl?cacy of insulin detemir (ll)et) and neutral protamine ltagedorn (NPlt) insulin and glargine in adults with type 1 diabetes. All trials were randomized, nonblinded, paral]el-gronp, mnlticenter studies, unless otherwise indicated. Mea]time bolus insulin was provided by rapid-acting insulin aspart, unless otherwise indicated. I)osages were titrated to achieve the same fasting g]ucose taNets in each trial. Analyses were intention-to-treat. (From Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitns. Drugs 2004;64:2577-95; with permission.) Baseline Study
Study duration
Home et aL 2004 [23]
Results at study end
Treatment
N
A I C (%)
(mg/dL)
A I C (%)
(mg/dL)
16
IDet BID :' IDet BID b NPH BID b
137 139 132
8.6 8.7 8.5
208 210 220
7.8 7.8 7.9
176" 161" 202
Pieber et al, 2005 [18]
26
IDet BID b IG QD °
161 159
8.8 8.8
8.2 8.2
139 126
Russell-J{mes et al, 2004 [19]
24
IDet QD cd NPH QD cd
491 256
8.4 8.4
214 208
8.3 8.4
185 i 205
Robertson eta], 2007 [26] ~
26
H)et QD c or BH) b NPtt QI) ~ o r B I I ) b
232 ] 15
8.8 8.7
202 200
8.0 7.9
151 173
Hennansen et aL 2004 [221
18
IDet BH) b NPH BH) bd
298 297
8.5 8.3
159 165
7.9* 8.1
136 146
K¢lendorf et al. 2006 [16[ df
16
H)et BIDg NPtt BI1)>
127 130
7.9 7.9
7.6 7.6
137 ~ 157
Pieber et al, 2005 [17]
16
IDet BID h IDet BID b NPH BID b
139 132 129
8.0 8.1 8.1
180 191 192
7.7 7.7 7.7
177 ~ 165 ~ 201
Standl et al, 20(14 [20] i
52
IDet BID d NPH BID d
154 134
7.7 7.7
196 196
7.9 7.8
182 177
Vague et al, 2003 [121]
26
H)et BII)g NPtt BIDS
301 146
8.2 8.1
209 209
7.6 7.6
165 179
De Leeuw eta], 2005 [151J
52
IDet BH)g NPH BH)g
216 99
8.2 8.0
211 207
7.6 7.6
193 194
Abbreviafions: A1C, glycosylated hemoglobin; IG. insulin glargine. ~%dministered every 12 hours. bAdministered in the morning mid at bedtime. ~'Administered at bedtime. dMealtime insulin requirement was provided by regular human insulin. e Trial in children and a&~lescents. fCrossover tria] consisting of two 16-week treatment periods. gAdministered before breakfast and at bedtime. hAdministered in the morning and at dinner. iExtenskm of Roberts et a [40] 6-month study. JExtension of Vague et a11121] 6-month study. "P < 0.001. -i-p = 0.001. ~P < 0.001. ~P < (1.(101 for overall comparison between the 3 treatment groups.
24
Endocrinology and Metabolism Clinics of North America
*
Supplement 1
[ ] NPH [ ] Insulin detemir
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*P < 0.001 ~P < 0.0001 Fig. I. Intrapatient wlriability (expressed as SD of fasting plasma glucose levels) in patients with type l diabetes treated with insulin detemir in clinical trials. NPH, neutral protamine Hagedorn; FPG, lasting plasma glucose; SI), standard dex.iation.
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Fig. z. Relative risk of nocturnal hypoglycemia in patients with type 1 diabetes treated with insulin detemir in clinical trials. NocttH'nal hypoglycemia was defined as any episode that occurred between 11 PM and 6 ~,a. Data presented for Home BID represent minor nocturnal hypoglycemic episodes. NPIt, neutral protamine Hagedorn.
Endocrinology and Metabolism Clinics of North America ® Supplement 1
multicenter, open-label, randomized, 2-armed, parallel group trial in 347 children and adolescents (mean age: 12 years). Patients were assigned to receive either insulin detemir or NPH insulin once or twice daily in addition to premeal insulin aspart. At the end of the study, A1C was reduced by 0.8% in both treatment groups and the mean difference between groups was not significant (0.09% [95% CI, -0.12 to 0.29]). However, although FPG was significantly lower in patients who received insulin detemir compared with those who received NPH insulin (151.9 vs 172.4 mg/dL, respectively; P = 0.022), the overall shape of the 8-point plasma glucose profiles and mean nocturnal plasma glucose levels were similar (P = 0.302 and P = 0.194, respectively). Children and adolescents with type 1 diabetes are at an increased risk of hypoglycemia as a result of insulin therapy; therefore, any improvement in intrapatient variability and incidence of hypoglycemia is of clinical importance [27,28]. lntrapatient variation in FPG was significantly lower m children and adolescents given insulin detemir than in those treated widl NPH insulin (SD 59.8 vs 77.2 ngldL, respectively; P < 0.001). hnportantly, the risk of nocturnal hypoglycemia was 36% lower with insulin detemir than with NPH insulin (P = 0.011), whereas die overall risk of hypoglycemia was similar with both treatments (P = 0.351) [261. Use of insulin detemir in patients with type 2 diabetes
The efficacy and safety of insulin detemir has been examined m 5 randomized clinical trials revolving more than 2500 patients with type 2 diabetes. The data from dlese trials are summarized in Table 2. In general, improvements in glycemic control observed with insulin detemir are accompanied by a reduced or equivalent risk of hypoglycemia m all comparative trials.
E.//icacy i~ pafiems wifh fype 2 diabefes Studies m patients with type 2 diabetes have shown that insulin detenfir, NPH insulin, and insulin glargme were equally effective ill optimizing A1C and FPG when added to oral antidiabetic drugs (OADs) in insulin-naive patients [29-31]. Interestingly, although insulin detemir and NPH insulin use resulted m a comparable number of patients (70%) achieving ta~et A1C levels of _<7%, more patients did so widlout experiencing hypoglycemia in the insulin detemir group (26% vs 16%; P = 0.008) [29]. In addition, compared with NPH insulin, insulin detenfir produces similar improvements m glycemic control, as measured by A1C levels, when given pre-breakfast or ill tile evening [31]. When compared with insulin glargme, insulin detemir provides smfilar levels of glycenfic control, intrapatient variability, and risk of hypoglycemia when added to OADs in insulinmaive patients widl type 2 diabetes [30]. Similarly, when used as part of a basalbolus regimen, insulin detemir is as effective as NPH
25
insulin in improving AI C and FPG in patients wifl~ type 2 diabetes [32,33].
SajeO, in patiems with f)~)e 2 diabefes Compared with NPH insulin, insulin detemir has been shown to reduce intrapatient variability m plasma glucose levels when given as part of a basal-bolus regimen [32,33]. ~lhe risk of hypoglycemia with insulin detemir was comparable to NPH insulin in patients treated with a basal-bolus regimen [32,33]. When insulin detemir was added to OAl)s in insulin-naive patients with type 2 diabetes, the relative risk of overall and nocturnal hypoglycemia was reduced by 47% ~md 55%, respectively, compared widl NPH insulin [29]. In addition to improved glycemic control accompanied by a reduced risk of hypoglycemia associated with insulin detemir, benefits ill terms of reduced weight gain have been reported. Notably, insulin detemir has been associated with significantly less weight gain than both NPH insulin and insulin glargme [29-33]. Tile results of these studies are discussed by Bush in more detail elsewhere m dlis supplement. Safety and ef[~cacy of insulin detemir in clinical practice
The PREDICTIVE study is a large, retrospective, openlabel, nolfinterventional study revolving juvenile and adult patients widl type 1 and type 2 diabetes from more than 20 countries, and is one of the la~est observational studies m diabetes. Tile study aims to evaluate the safety mid efficacy of insulin detemir when used m routine cliifical practice, and to collect information cm treatment patterns and glycemic control m diabetes. The study is ongoing and, as of March 2006, more than 30,000 patients m Europe, North America, Soudl America, Africa, Asia, and die Middle East have been included m the study. Results i?om die Germ~m cohort of the PREDICTIVE study, which i,mlude data from 10,276 patients, have shown that insulin detemir improves glycemic control (Fig. 3), improves mtrapadent vmiability in glucose response (Fig. 4A), reduces d~e incidence of hypoglycemia (Figs. 4B, C, D), and maintains weight Imutrality after 3 mondls of treaUnent [34,351. Various subgroup analyses from the German cohort of the PREDICTIVE study have shown that insulin detelifir can improve glycemic control and reduce tile incidence of hypoglycemia irrespective of prior treatment regimens (Table 3) [34,36-39]. Insulin detemir has been shown to be effective in patients widl type 1 diabetes previously treated with all all-human-insulin [38] or NPH-based [39] basal-bolus regimen. Similarly, improvements m glycemic control and safety were reported in patients with type 2 diabetes switching from basal-bolus therapy with NPH insulin [39], therapy with NPH or insulin glargine as basal-only insulin + ()ADs [36], and l?om a
26
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Fig 5. Percentage of patients with a glycosylated hemoglobin (A1C) <7% at baseline and after 3 months in patients transitioning from oral antidiabetic drag (OAD)-only regimens (n = 1118), neutrM protamine ttagedorn (NPtt) insulin _+OADs (n = 206), or insulin glargine _+OADs (n = 216) to insulin detemir _+ ()ADs. *P < 0.0001. (F}'om Meneghini I,F, Rosenberg KH, Koenen (Let M. Insu]in detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREI)IC ['IVE stu@. Diabetes Obes Metab. 2007;9:418-27, with permission.).
regimen of OADs alone (poorly controlled, insulin-naive patients) [34,37]. Furthermore, at 3 months after switching from treatment with NPH insulin, insulin glargine, or OAD mono~lerapy, the proportions of patients with an A1C <7% were significantly greater compared with baseline (all, P < 0.001) (Fig. 5) [34]. Therefore, results from the German cohort of the PREDICTIVE study support and confirm some of the key observations from prior clinical studies with insulin detemir. Summary
Presently, d~e majority of patients with diabetes are not achievhlg glycemic targets. Hypoglycemia renmins a concern lk~rpatients and health care professionals and can hinder the pursuit of good glycemic control. Therefore, there is a need to integrate improved insulin therapies, such as insulin detemir, hlto cli,fical practice to help more patients move safely toward glycenfic ta~ets. Acknowledgment
Philip Raskin, MD, thalks Steven Burke, PhD, of Complete Medical Co~mnmfications, who provided medical writing support funded by Novo Nordisk Inc. correspondence to: Philip Raskin, MD, Professor of Internal Medichle-Endocrhlology, Clifton and Betsy Robinson Chair in Biomedical Research, U~fiversity of Texas Southwestern MeNcal Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8858. Emmil: [email protected] Address
References Ill The l)iabetes Control and Complica6ons 'I~ial Research Group. The effect of intensive ueatment of diabetes on the development and progression of long-term complica6ons in insulin-dependent diabetes mellims. N Engl J Med 1993;329:977-86. [2] UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonyM'eas or insulin compared with conventionM treatment and risk of complications in patients wiLh type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. [3] Stratton IM, Adler A[, Nell HA, et al. Association of glycaemia with macrovascnlar and microvascular complications of type 2 diabetes (UKPI)S 35): prospective observational study. BMJ 2000;321: 405-12. [4] American Association of Clinical Endocrinologists. American College of Endocrinology consensus statement on gtfidelines for glyce~mc control. Available at: http://www.aace.congmeedngs/consensus/dcc/pdf/ dccwhitepaper.pdL Accessed September 26~ 2006. [5] Nathan DM, Buse JB, Davidson 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 Associa6on and the European Assoda6on for the Study of Diabetes. Diabetes Care 2006;29:1963-72. [6] State of Diabetes in America TM Report. Avmlable at: http://www. aace.com/public/awareness/stateofdiabetes/Diabetes.~nericaReport.pdf. Accessed September 26, 2006. [7] Koro CE, Bowlin SL Bourgeois N, Feddcr DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care 2004;27:17-20. [8] Cryer PE. HypoglycaeiNa: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 2002;45:937-48. [9] The ACE/ADA Task Force on Inpatient Diabetes. American College of Endocrinology and American Diabetes Association consensus statement on inpatient diabetes and glycemic control. A cM1 to action. l)iabetes Care 2006;29:1955-62.
Endocrinology and Metabolism Clinics of North America
[10] The Diabetes Control and Complications Trial Research Group. The absence ol a glycemic threshold for the development (3t' long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 1996;45:1289-98. [11] Heller S, Olsen KJ, Draeger E. Within-pe.rson w~riation in fasting blood glucose is coLrelated to incidence of hypoglycemia in people with type 1 diabetes treated with insulin detemir and NPH. 64th Annum Scientific Sessions of the American Diabetes Association; June 4-8, 2004; Orlando, b]orida. Abstract A2037-PO. [12] Muggeo M, Zoppini G, Bonora E, et M. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care 2000;23:45-50. [13] Kurtzhals R Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir Int J Obes 2004;28(Suppl 2):$23-8. [14] Chapman TM. Perry CM. lnsNin detemir: a review (3t'its use in the management of type 1 and 2 diabetes mellims. Drugs. 2004;64: 2577-95. [15] De Leeuw I, Vague R Selam J-L, et aL Insulin deteiNr used in basMbolus therapy in people with Vpe 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 moNhs in comparison to NPII insulin. Diabetes Obes Metab 2005;7:73-82. [16] K¢lendoff K, Ross GR Pavlic-Renar I, et al. Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH insulin in type I diabetes, l)iabet Med 2006;23:729-35. [17] Pieber TR, Draeger E, Kristensen A, Grill \( Comparison of three multiple ii~jection regimens for type 1 diabetes: morning plus dinner or bedtime adiNnistration of insulin detemir vs. morning plus bedtime NPtt instflin. Diabet Med 2005;22:850-7. [18] Pieber TR, 'IS:eichel H-C, Robertson LI, et al. Insufin detemir plus insulin aspart is associated with less risk of major as well as nocturnN hypoglycaemia than insulin glargine plus insulin aspart at comparable levels of glycaemic control in type 1 diabetes. Diabetologia 2005; 48:A92. AbstLact. [19] Russell-Jones D, Simpson R, IIylleberg B, et M. Effects of QD insulin deIeiNr 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. [20] Standl E, I,ang H, Robelxs A. [qae 12-month efficacy and safety of insulin detemir and NPH insulin in basal-bolus therapy for the treatment of type 1 diabetes. DiabeIes Technol Ther 2004;6:579-88. [21] Vague R Selam J-L, Skeie S, et aL Insulin detemir is associated with more predictable glyce~mc coNrol and reduced risk of hypoglyce~Na than NPII insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 2003;26:590-6. [22] Hermansen K, Fontaine R K u b l j a KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with Vpe 1 diabetes. Diabetologia 2004;47:622-9. [23] Home R Bartley R Russell-Jones D, et aL Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 2(t04;27: 1081-7. [24] Heller S, tlansoo K. Insulin deten-fir reduces hypoglycemic risk at comparable tibAlc values compared to NPH in patients with Vpe 1 diabetes. 65th Annual Scientific Sessions of the American Diabetes Association; June 10-14, 2005; San Diego, CMifornia. Abstract. [25] Russell-Jones D, Kim It, Heller S, Clauson R Insulin detemir reduces the risk of hypoglycemia at all levels of HbAlc compared to NPH
[26]
[27] [28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
® Supplement 1
31
insulin in the context of basal bolus therapy tk)r type I diabetes. Diabetologia 2005;48:A92. Abstract. Robertson KJ. Sch~Snle E, Gucev Z. et al. Insulin detemir compared with NPH insulin in chil&en and adolescents with type I dmbetes. Diabet Med 2007;24:27-34. Matyka K, Ford-Adams M, Dunger DB. Hypoglycaemia and counterregulatkm during childhood. Horm Res 2002;57(Suppl 1 ):85-90. The Diabetes Control and Complications Trim Research Group. Hypoglycemia in the Diabetes Control and Complications TriM. Diabetes 1997;46:271-86. Hermansen K, Davies M, Derezinsld 3, et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPtt insulin as add-on therapy to oral glucose-lowering drugs in insulinnaive people with type 2 diabetes. Diabetes Care 2006;29:1269-74. Rosenstock J, Davies M, ttome PD, et al. Insulin detemir added to oral anti-diabetic &ugs in type 2 diabetes provides glycemic control comparal)le to insulin glargine with less weight gain. Dmbetes 2006;55(Suppl):A132. Abstract. Philis- ['simikas A, Chal~entier G, Clauson R et M. Comparison of once-daily insulin detemir with NPtt insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569-81. Ilaak T, Tiengo A, Draeger E, et al. Lower within-subiect variability of fasting Nood glucose and reduced weight gain with insulin detemir compared to NPtt instflin in patients with type 2 diabetes. Diabetes Obes Metab 2005 ;7:5(¢-64. Ra,~lovfi K, Bogoev M, Raz I, et aL Insulin detemir and insulin ~part: a promising basM-bolus regimen for type 2 diabetes. Diabetes Res Clin lh'act 2004;66:193-201. Meneghini LF, Rosenberg KIt, Koenen C, et al. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPtt or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab 2007;9:418-27. Ltiddeke H-J, Hansen JB, Merilalnen M, Gallwitz B. An evaluation of insulin detemir treatment in type 1 and type 2 diabetes: German cohort data frum the PREDICTIVE study. 42nd Annual Meeting of the European Association for the Sin@ of Diabetes; September 14-17, 2006; Copenhagen, Denmark. Abstract. l)ornhorst A, Merilainen M. Ratzmann KP. Insulin detemir with or without OAD improves glycemic control and re&ices hypoglycemic epsidoes, without weight gain, in type 2 diabetes patients previously treated with NPII or glargine: results from a German subgroup of PREDICTIVE. Diabetes 2006;55(Suppl I):A 146. Abstract. Dornhorst A, Merilainen M, Ratzmann KR hlitiating insulin detemir improves glycemic control without weight gain in OAD-treated insulin naive patients with type 2 diabetes: results from a German subgroup of the PREDICTIVE study. Diabetes 2006;55(Suppl I):AI l/l. Abstl"act. Maxeiner S, Hansen JB, Nauck M. Switching from a human insulin basal-bohls regimen to insulin analog basal-bolus therapy with insulin detemir/insulin aspart improves glyceiNc control and reduces hypoglycemic episodes in patients with type 1 diabetes: results from German subgroup of the PREDICTIVI~; TM study. 66th Annual Scientific Sessions of the American Diabetes Association; Jm3e 9-13, 2006; Washington, DC. Ruhnall KJ, ttansen JB, Dornhorst A. Switching from basal-bolus therapy with NPH insulin to basM-bolus therapy with the anMog insulin detemir improves glyceiNc control and reduces hypoglycemic episodes, without weight gain in type I and type 2 diabetes patients:
32
Endocrinology and Metabolism Clinics of North America results from German subgroup of the PREDICTIVE sin@. 66th Annual Scientific Sessions of tile American Diabetes Association; June 9-13, 2006; Washington, DC.
* Supplement 1
[40] Roberts A, Standl E, Bayer T, et al. Efficacy and safety of 6-month treatment with insulin deteiNr in type 1 diabetic patients on a basMbolus regimen. Diabetologia 2001;44(Suppl 1):A207. Abstract.
~ E R
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[]
|n|CS
SAUNDERS
Efficacy and Safety of Insulin Detemir Philip Raskin, MD Professor of Internal Medicine-Endocriaolog3; Clifton and Betsy Robinson Chair in Biomedical Research, U~Tiversity qf 7~xas Southwestern Medical Center at Dallas, Dallas, 7>xas
In the treatment of patients with diabetes, the tear of hypoglycemia is a major barrier to initiating, maintaining, and/or intensifying insulin therapy. Insulin detemir (Levemir ® [Novo Nordisk A/S, Bagsvaerd, Denmark]) is a novel, long-acting, basal insulin analog associated with a reduced risk of hypoglycemia that is available to improve glycemic control. This article discusses clinical trial data on the safety and efficacy of insulin detemir in patients with type I and type 2 diabetes. In addRhm, results from the German cohort of the Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation (PREDICTIVE TM)study, a large, multinational observational study examining the clinical effectivehess and safety of insulin detemir, are reviewed. Finally, an evaluation of these data serves to show how the highly predictable action of insulin detemir translates into effective glycemic control with a lower incidence of hypoglycemia. Diabetes mellitus is a chronic disease that is characterized by hype~lycemia. Patients with type 1 diabetes exhibit al absolute or severe deficiency m insulin secretion aid require the ad~mfistration of exogenous insulin for survival. Type 2 diabetes is characterized by a combination of insulin deficiency and insulin resistance, and is often i,fitially controlled by dietau modification, an increase in physical activity, and oral antihyperglycemic agents. However, those patients who cannot maintain adequate glycemic control often require insulin therapy as file disease progresses. Intensive therapy to normalize blood glucose levels has been shown to substantially reduce the microvascular complicaticms associated with type 1 ~mdtype 2 diabems [1-31, Subsequently, individual targets for glycemic control have been set by both tile American Diabetes Association (ADA) arid the American Association of Clhfical Endocrinologists (AACE) [4,5]. Tile ADA currently recommends a target glycosylated hemoglobin (A1C) of <7% for patients in general, but reco,lunends that eadl patient achieve an A1C as close m normal (6%) as possible. Tile AACE suggests aiming ibr a target of 6.5% or lower. Tile ADA also proposes a target range for l:astmg plasma glucose (FPG) levels between 70 and 130 ng/dL, whereas the AACE reconnnends levels below 110 ~IN/dL. Tile m~iority of patients with diabetes are not achieving adequate glycemic control [6] and it is thought that the risk of hypoglycemia is the primary obstacle [6-8]. Indeed, among both patiems with diabetes arid health care profes-
sionals, hypoglycemia is one of tile most feared consequences of intensive insulin therapy [9]. Results from tile Diabetes Control and Complications Trial show that, as patiems approach target A1C levels, there is a 26% increase in the risk of hypoglycemia for each 1% reduction in A1C [10]. Tile inci&nce of hypoglycemia has been correlated with variability m blood glucose response to insulin [111. In addition, variability in blood glucose has been established as an independent risk factor for mortality [12]. Recently, the acylation of fatty acids to the insulin molecule has cuhninated m the clinical availability of insulin detemir. Insulin detemir is a neutral, soluble, long-acting insulin analog for*ned by the removal of tile amino acid threonine at file B30 locus and the acylation of a 14-carbon fatty acid (myristic acid) to lysine at locus B29 [131. Tile acylation of a fatty acid to the insulin molecule stabilizes self-association into dihexamers and permits reversible insulin-albmifin binding that, together, am thought to mediate its slow absorption from the subcutaneous depot and prolong its duration of action [13]. Tile unique albumin binding properties of insulin dete,ifir contribute to a significant reduction in intrapatient variability of pharmacokinetic and pharmacodynamic profles compared with other basal insulin preparations [13[, which is discussed further by Kurtzhals hi this supplement. Dr. Raskin is on the Advisory Board of Novo Nol'disk and has received a grant from sanofi-aventis.
22
Endocrinology and Metabolism Clinics of North America * Supplement 1
This article reviews the efficacy and safety of insulin detemir in patients with type I and type 2 diabetes, and examines the clinical benefits of its unique pharmacodynamic profile. Efficacy and safety of insulin detemir in patients with type 1 diabetes
~II~e efficacy and safety of insulin detemir have been examined in more than 3500 patients wifl~ type 1 diabetes in 11 trials (10 randomized, parallel, controlled trials and 1 crossover study), the results of which are discussed here. In general, the improvements in glycemic control observed with insulin detemir were accompanied with a reduced or similar risk of hypoglycemia in all comparative trials. P.i~ticacy in pafients wifh O'Pe I diabetes Overall, the level of metabolic control achieved with insulin detemir, as assessed by A1C levels, is comparable to that achieved with neutral protamine Hagedom (NPH) insulin (Table 1) and insulin glargine [14-21]. In 2 of tile studies, A1C levels were significantly lower m patients receiving insulin detemir compared with those receiving NPH insulin [22,23]. Insulin detemir has been shown to improve fasting glucose levels and effect more consistent blood glucose profiles than NPH insulin. In a 16-week dose-timing study, FPG levels were lower m patients receiving insulin detemir than in dlose receiving NPH insulin, irrespective of dosing regimen employed (P = 0.006) [171. At the end of another 16-week study, FPG was lower m patients randomized to receive insulin detemir every 12 hours (-27.0 mg/dL vs NPH [95% CI, -45.2 to -8.61; P = 0.004) or m tile morning and at bedtime (-41.4 mg/dL [-59.8 to -23.2]; CI, P < 0.001); compared with NPH insulin administered before breakfast and at bedtime [23]. Further, insulin detemir, with regular human insulin at mealtimes, led to reductions m bodl FPG (-29.0 mg/dL, P = 0.001) and the 9-point self-measured plasma glucose profiles, compared with NPH insulin in combination with regular human insulin (P = 0.006) [19]. Basal-bolus insulin therapy widl all all-analog regimen led to improvements m 8-point plasma glucose profiles and postprandial glucose excursions, compared widl a human insulin-based regimen [22]. Moreover, an analysis of die 10-point glucose profile by Pieber et al [17], demonstrated that nocturnal glucose levels were lower m patients receiving insulin detemir than in those treated widl NPH insulin (P = 0.043). In addition, the results from continuous glucose molfitoring co~Nrmed flatter and more consistent nocturnal glucose levels in patients treated with insulin detemir [17]. To date, only 1 stu@ has directly compared die effects of insulin detemir and insulin gla~ine m patients with type 1 diabetes [181. The results from this 26-week study
suggest fl~at insulin detemir is as effective as insulin glargine in improving AIC and produces a similar 9-point plasma glucose profile [181. In summary, these studies demonstrate that insulin detemir is as effective as NPH insulin and insulin glargine in establishing and maintaining glycemic control. Sajea, in patienf~~wi#z f3~)e l diabefes A number of studies in patients with type 1 diabetes have demonstrated that treatment with insulin detemir results in a low risk of hypoglycemia, particularly, nocturnal hypoglycemia [ 15,16,19,21-23] (Fig. 1), and reduced intrapatient variability in FPG [16,17,19,21-23] (Fig. 2) compared with NPH insulin. Interestingly, it has been reported recently that the reduction in intrapatient FPG variability is a major contributor to tile reduced risk of nocturnal hypoglycemia observed with insulin detemir relative to NPH insulin [11]. A recent pooled analysis i?om 4 multicenter, randomized, clinical trials involving 1180 patients receiving insulin detemir and 810 patients receiving NPH illustrated that tile relative risk of hypoglycemia was 22% lower in patients randomized to insulin detemir (P < 0.001) [24,25]. Furfllermore, compared with NPH, insulin detemir was associated with a lower risk of hypoglycemia at all A1C levels, which suggests that insulin detenfir may allow more patients to achieve effective glycemic control with a lower associated risk of hypoglycemia [24,251. In a 6-month clinical trial comparing insulin detemir with NPH insulin, the significant reduction in intrapadent variability (P < 0.001) observed m patients receiving insulin detemir was accompanied wifll a 22% reduction m tile overall risk of hypoglycemia (P < 0.05) and a 34% reduction in the risk of nocturnal hypoglycemia (P < 0.005) relative to NPH insulin [21]. There were fewer hypoglycemic events in a 6-month extension of the study, and the risk of nocturnal hypoglycemia was 32% lower (P = 0.02) with insulin detemir than with NPH insulin [151. In addition, insulin detemir significantly reduced intrapatient variation m FPG values (P < 0.001) and reduced the risk of nocturnal hypoglycemia (-26%; P = 0.003) compared with NPH insulin when used in basal-bolus therapy with mealtime human insulin for 6 mondls [19]. Tile only study to report tile risk of hypoglycemia as its primary end point is a crossover study consisting of two 16-week treatment periods with either insulin detemir or NPH insulin in combination widl premeal insulin aspart [16]. In this study, a 50% reduction m nocturnal hypoglycemia (P < 0.0001) and an 18% reduction in overall hypoglycemia (P = 0.001) was observed with insulin detemir relative to NPH insulin and was accompanied by a reduction m mtrapatient variation in FPG (P < 0.001) [16].
Endocrinology and Metabolism Clinics of North America
When compared with insulin glargine, insulin detemir significantly reduced intrapatient variability in predinner plasma glucose (P < 0.05) and reduced the risk of both major (-72%) and nocturnal (-32%) hypoglycemia (P < 0.05) [181.
® Supplement 1
23
Efficacy and safeO" in children and adolescents with O'pe 1 diabetes One study has examined the efficacy and safety of insulin detemir in children and adolescents [26]. Robertson et al [26] presented the results of a 26-week,
~[hble 1 Efl?cacy of insulin detemir (ll)et) and neutral protamine ltagedorn (NPlt) insulin and glargine in adults with type 1 diabetes. All trials were randomized, nonblinded, paral]el-gronp, mnlticenter studies, unless otherwise indicated. Mea]time bolus insulin was provided by rapid-acting insulin aspart, unless otherwise indicated. I)osages were titrated to achieve the same fasting g]ucose taNets in each trial. Analyses were intention-to-treat. (From Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitns. Drugs 2004;64:2577-95; with permission.) Baseline Study
Study duration
Home et aL 2004 [23]
Results at study end
Treatment
N
A I C (%)
(mg/dL)
A I C (%)
(mg/dL)
16
IDet BID :' IDet BID b NPH BID b
137 139 132
8.6 8.7 8.5
208 210 220
7.8 7.8 7.9
176" 161" 202
Pieber et al, 2005 [18]
26
IDet BID b IG QD °
161 159
8.8 8.8
8.2 8.2
139 126
Russell-J{mes et al, 2004 [19]
24
IDet QD cd NPH QD cd
491 256
8.4 8.4
214 208
8.3 8.4
185 i 205
Robertson eta], 2007 [26] ~
26
H)et QD c or BH) b NPtt QI) ~ o r B I I ) b
232 ] 15
8.8 8.7
202 200
8.0 7.9
151 173
Hennansen et aL 2004 [221
18
IDet BH) b NPH BH) bd
298 297
8.5 8.3
159 165
7.9* 8.1
136 146
K¢lendorf et al. 2006 [16[ df
16
H)et BIDg NPtt BI1)>
127 130
7.9 7.9
7.6 7.6
137 ~ 157
Pieber et al, 2005 [17]
16
IDet BID h IDet BID b NPH BID b
139 132 129
8.0 8.1 8.1
180 191 192
7.7 7.7 7.7
177 ~ 165 ~ 201
Standl et al, 20(14 [20] i
52
IDet BID d NPH BID d
154 134
7.7 7.7
196 196
7.9 7.8
182 177
Vague et al, 2003 [121]
26
H)et BII)g NPtt BIDS
301 146
8.2 8.1
209 209
7.6 7.6
165 179
De Leeuw eta], 2005 [151J
52
IDet BH)g NPH BH)g
216 99
8.2 8.0
211 207
7.6 7.6
193 194
Abbreviafions: A1C, glycosylated hemoglobin; IG. insulin glargine. ~%dministered every 12 hours. bAdministered in the morning mid at bedtime. ~'Administered at bedtime. dMealtime insulin requirement was provided by regular human insulin. e Trial in children and a&~lescents. fCrossover tria] consisting of two 16-week treatment periods. gAdministered before breakfast and at bedtime. hAdministered in the morning and at dinner. iExtenskm of Roberts et a [40] 6-month study. JExtension of Vague et a11121] 6-month study. "P < 0.001. -i-p = 0.001. ~P < 0.001. ~P < (1.(101 for overall comparison between the 3 treatment groups.
24
Endocrinology and Metabolism Clinics of North America
*
Supplement 1
[ ] NPH [ ] Insulin detemir
-o
& k~ 0LL.
C3 L/) >,.
~=
*P < 0.001 ~P < 0.0001 Fig. I. Intrapatient wlriability (expressed as SD of fasting plasma glucose levels) in patients with type l diabetes treated with insulin detemir in clinical trials. NPH, neutral protamine Hagedorn; FPG, lasting plasma glucose; SI), standard dex.iation.
[ ] NPH [ ] Insulin detemir [ ] Insulin glargine
1.2-
E
m.0-
IN) O ¢a
=~
0.8-
E
8 ~6 v
0,6-
0.4-
"r" O9
._>
_~
0.2-
o
O-
*P < 0.05 *)
~N
Fig. z. Relative risk of nocturnal hypoglycemia in patients with type 1 diabetes treated with insulin detemir in clinical trials. NocttH'nal hypoglycemia was defined as any episode that occurred between 11 PM and 6 ~,a. Data presented for Home BID represent minor nocturnal hypoglycemic episodes. NPIt, neutral protamine Hagedorn.
Endocrinology and Metabolism Clinics of North America ® Supplement 1
multicenter, open-label, randomized, 2-armed, parallel group trial in 347 children and adolescents (mean age: 12 years). Patients were assigned to receive either insulin detemir or NPH insulin once or twice daily in addition to premeal insulin aspart. At the end of the study, A1C was reduced by 0.8% in both treatment groups and the mean difference between groups was not significant (0.09% [95% CI, -0.12 to 0.29]). However, although FPG was significantly lower in patients who received insulin detemir compared with those who received NPH insulin (151.9 vs 172.4 mg/dL, respectively; P = 0.022), the overall shape of the 8-point plasma glucose profiles and mean nocturnal plasma glucose levels were similar (P = 0.302 and P = 0.194, respectively). Children and adolescents with type 1 diabetes are at an increased risk of hypoglycemia as a result of insulin therapy; therefore, any improvement in intrapatient variability and incidence of hypoglycemia is of clinical importance [27,28]. lntrapatient variation in FPG was significantly lower m children and adolescents given insulin detemir than in those treated widl NPH insulin (SD 59.8 vs 77.2 ngldL, respectively; P < 0.001). hnportantly, the risk of nocturnal hypoglycemia was 36% lower with insulin detemir than with NPH insulin (P = 0.011), whereas die overall risk of hypoglycemia was similar with both treatments (P = 0.351) [261. Use of insulin detemir in patients with type 2 diabetes
The efficacy and safety of insulin detemir has been examined m 5 randomized clinical trials revolving more than 2500 patients with type 2 diabetes. The data from dlese trials are summarized in Table 2. In general, improvements in glycemic control observed with insulin detemir are accompanied by a reduced or equivalent risk of hypoglycemia m all comparative trials.
E.//icacy i~ pafiems wifh fype 2 diabefes Studies m patients with type 2 diabetes have shown that insulin detenfir, NPH insulin, and insulin glargme were equally effective ill optimizing A1C and FPG when added to oral antidiabetic drugs (OADs) in insulin-naive patients [29-31]. Interestingly, although insulin detemir and NPH insulin use resulted m a comparable number of patients (70%) achieving ta~et A1C levels of _<7%, more patients did so widlout experiencing hypoglycemia in the insulin detemir group (26% vs 16%; P = 0.008) [29]. In addition, compared with NPH insulin, insulin detenfir produces similar improvements m glycemic control, as measured by A1C levels, when given pre-breakfast or ill tile evening [31]. When compared with insulin glargme, insulin detemir provides smfilar levels of glycenfic control, intrapatient variability, and risk of hypoglycemia when added to OADs in insulinmaive patients widl type 2 diabetes [30]. Similarly, when used as part of a basalbolus regimen, insulin detemir is as effective as NPH
25
insulin in improving AI C and FPG in patients wifl~ type 2 diabetes [32,33].
SajeO, in patiems with f)~)e 2 diabefes Compared with NPH insulin, insulin detemir has been shown to reduce intrapatient variability m plasma glucose levels when given as part of a basal-bolus regimen [32,33]. ~lhe risk of hypoglycemia with insulin detemir was comparable to NPH insulin in patients treated with a basal-bolus regimen [32,33]. When insulin detemir was added to OAl)s in insulin-naive patients with type 2 diabetes, the relative risk of overall and nocturnal hypoglycemia was reduced by 47% ~md 55%, respectively, compared widl NPH insulin [29]. In addition to improved glycemic control accompanied by a reduced risk of hypoglycemia associated with insulin detemir, benefits ill terms of reduced weight gain have been reported. Notably, insulin detemir has been associated with significantly less weight gain than both NPH insulin and insulin glargme [29-33]. Tile results of these studies are discussed by Bush in more detail elsewhere m dlis supplement. Safety and ef[~cacy of insulin detemir in clinical practice
The PREDICTIVE study is a large, retrospective, openlabel, nolfinterventional study revolving juvenile and adult patients widl type 1 and type 2 diabetes from more than 20 countries, and is one of the la~est observational studies m diabetes. Tile study aims to evaluate the safety mid efficacy of insulin detemir when used m routine cliifical practice, and to collect information cm treatment patterns and glycemic control m diabetes. The study is ongoing and, as of March 2006, more than 30,000 patients m Europe, North America, Soudl America, Africa, Asia, and die Middle East have been included m the study. Results i?om die Germ~m cohort of the PREDICTIVE study, which i,mlude data from 10,276 patients, have shown that insulin detemir improves glycemic control (Fig. 3), improves mtrapadent vmiability in glucose response (Fig. 4A), reduces d~e incidence of hypoglycemia (Figs. 4B, C, D), and maintains weight Imutrality after 3 mondls of treaUnent [34,351. Various subgroup analyses from the German cohort of the PREDICTIVE study have shown that insulin detelifir can improve glycemic control and reduce tile incidence of hypoglycemia irrespective of prior treatment regimens (Table 3) [34,36-39]. Insulin detemir has been shown to be effective in patients widl type 1 diabetes previously treated with all all-human-insulin [38] or NPH-based [39] basal-bolus regimen. Similarly, improvements m glycemic control and safety were reported in patients with type 2 diabetes switching from basal-bolus therapy with NPH insulin [39], therapy with NPH or insulin glargine as basal-only insulin + ()ADs [36], and l?om a
26
E n d o c r i n o l o g y and M e t a b o l i s m Clinics o f N o r t h A m e r i c a
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Fig 5. Percentage of patients with a glycosylated hemoglobin (A1C) <7% at baseline and after 3 months in patients transitioning from oral antidiabetic drag (OAD)-only regimens (n = 1118), neutrM protamine ttagedorn (NPtt) insulin _+OADs (n = 206), or insulin glargine _+OADs (n = 216) to insulin detemir _+ ()ADs. *P < 0.0001. (F}'om Meneghini I,F, Rosenberg KH, Koenen (Let M. Insu]in detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREI)IC ['IVE stu@. Diabetes Obes Metab. 2007;9:418-27, with permission.).
regimen of OADs alone (poorly controlled, insulin-naive patients) [34,37]. Furthermore, at 3 months after switching from treatment with NPH insulin, insulin glargine, or OAD mono~lerapy, the proportions of patients with an A1C <7% were significantly greater compared with baseline (all, P < 0.001) (Fig. 5) [34]. Therefore, results from the German cohort of the PREDICTIVE study support and confirm some of the key observations from prior clinical studies with insulin detemir. Summary
Presently, d~e majority of patients with diabetes are not achievhlg glycemic targets. Hypoglycemia renmins a concern lk~rpatients and health care professionals and can hinder the pursuit of good glycemic control. Therefore, there is a need to integrate improved insulin therapies, such as insulin detemir, hlto cli,fical practice to help more patients move safely toward glycenfic ta~ets. Acknowledgment
Philip Raskin, MD, thalks Steven Burke, PhD, of Complete Medical Co~mnmfications, who provided medical writing support funded by Novo Nordisk Inc. correspondence to: Philip Raskin, MD, Professor of Internal Medichle-Endocrhlology, Clifton and Betsy Robinson Chair in Biomedical Research, U~fiversity of Texas Southwestern MeNcal Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8858. Emmil: [email protected] Address
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[10] The Diabetes Control and Complications Trial Research Group. The absence ol a glycemic threshold for the development (3t' long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 1996;45:1289-98. [11] Heller S, Olsen KJ, Draeger E. Within-pe.rson w~riation in fasting blood glucose is coLrelated to incidence of hypoglycemia in people with type 1 diabetes treated with insulin detemir and NPH. 64th Annum Scientific Sessions of the American Diabetes Association; June 4-8, 2004; Orlando, b]orida. Abstract A2037-PO. [12] Muggeo M, Zoppini G, Bonora E, et M. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care 2000;23:45-50. [13] Kurtzhals R Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir Int J Obes 2004;28(Suppl 2):$23-8. [14] Chapman TM. Perry CM. lnsNin detemir: a review (3t'its use in the management of type 1 and 2 diabetes mellims. Drugs. 2004;64: 2577-95. [15] De Leeuw I, Vague R Selam J-L, et aL Insulin deteiNr used in basMbolus therapy in people with Vpe 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 moNhs in comparison to NPII insulin. Diabetes Obes Metab 2005;7:73-82. [16] K¢lendoff K, Ross GR Pavlic-Renar I, et al. Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH insulin in type I diabetes, l)iabet Med 2006;23:729-35. [17] Pieber TR, Draeger E, Kristensen A, Grill \( Comparison of three multiple ii~jection regimens for type 1 diabetes: morning plus dinner or bedtime adiNnistration of insulin detemir vs. morning plus bedtime NPtt instflin. Diabet Med 2005;22:850-7. [18] Pieber TR, 'IS:eichel H-C, Robertson LI, et al. Insufin detemir plus insulin aspart is associated with less risk of major as well as nocturnN hypoglycaemia than insulin glargine plus insulin aspart at comparable levels of glycaemic control in type 1 diabetes. Diabetologia 2005; 48:A92. AbstLact. [19] Russell-Jones D, Simpson R, IIylleberg B, et M. Effects of QD insulin deIeiNr 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. [20] Standl E, I,ang H, Robelxs A. [qae 12-month efficacy and safety of insulin detemir and NPH insulin in basal-bolus therapy for the treatment of type 1 diabetes. DiabeIes Technol Ther 2004;6:579-88. [21] Vague R Selam J-L, Skeie S, et aL Insulin detemir is associated with more predictable glyce~mc coNrol and reduced risk of hypoglyce~Na than NPII insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 2003;26:590-6. [22] Hermansen K, Fontaine R K u b l j a KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with Vpe 1 diabetes. Diabetologia 2004;47:622-9. [23] Home R Bartley R Russell-Jones D, et aL Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 2(t04;27: 1081-7. [24] Heller S, tlansoo K. Insulin deten-fir reduces hypoglycemic risk at comparable tibAlc values compared to NPH in patients with Vpe 1 diabetes. 65th Annual Scientific Sessions of the American Diabetes Association; June 10-14, 2005; San Diego, CMifornia. Abstract. [25] Russell-Jones D, Kim It, Heller S, Clauson R Insulin detemir reduces the risk of hypoglycemia at all levels of HbAlc compared to NPH
[26]
[27] [28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
® Supplement 1
31
insulin in the context of basal bolus therapy tk)r type I diabetes. Diabetologia 2005;48:A92. Abstract. Robertson KJ. Sch~Snle E, Gucev Z. et al. Insulin detemir compared with NPH insulin in chil&en and adolescents with type I dmbetes. Diabet Med 2007;24:27-34. Matyka K, Ford-Adams M, Dunger DB. Hypoglycaemia and counterregulatkm during childhood. Horm Res 2002;57(Suppl 1 ):85-90. The Diabetes Control and Complications Trim Research Group. Hypoglycemia in the Diabetes Control and Complications TriM. Diabetes 1997;46:271-86. Hermansen K, Davies M, Derezinsld 3, et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPtt insulin as add-on therapy to oral glucose-lowering drugs in insulinnaive people with type 2 diabetes. Diabetes Care 2006;29:1269-74. Rosenstock J, Davies M, ttome PD, et al. Insulin detemir added to oral anti-diabetic &ugs in type 2 diabetes provides glycemic control comparal)le to insulin glargine with less weight gain. Dmbetes 2006;55(Suppl):A132. Abstract. Philis- ['simikas A, Chal~entier G, Clauson R et M. Comparison of once-daily insulin detemir with NPtt insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569-81. Ilaak T, Tiengo A, Draeger E, et al. Lower within-subiect variability of fasting Nood glucose and reduced weight gain with insulin detemir compared to NPtt instflin in patients with type 2 diabetes. Diabetes Obes Metab 2005 ;7:5(¢-64. Ra,~lovfi K, Bogoev M, Raz I, et aL Insulin detemir and insulin ~part: a promising basM-bolus regimen for type 2 diabetes. Diabetes Res Clin lh'act 2004;66:193-201. Meneghini LF, Rosenberg KIt, Koenen C, et al. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPtt or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab 2007;9:418-27. Ltiddeke H-J, Hansen JB, Merilalnen M, Gallwitz B. An evaluation of insulin detemir treatment in type 1 and type 2 diabetes: German cohort data frum the PREDICTIVE study. 42nd Annual Meeting of the European Association for the Sin@ of Diabetes; September 14-17, 2006; Copenhagen, Denmark. Abstract. l)ornhorst A, Merilainen M. Ratzmann KP. Insulin detemir with or without OAD improves glycemic control and re&ices hypoglycemic epsidoes, without weight gain, in type 2 diabetes patients previously treated with NPII or glargine: results from a German subgroup of PREDICTIVE. Diabetes 2006;55(Suppl I):A 146. Abstract. Dornhorst A, Merilainen M, Ratzmann KR hlitiating insulin detemir improves glycemic control without weight gain in OAD-treated insulin naive patients with type 2 diabetes: results from a German subgroup of the PREDICTIVE study. Diabetes 2006;55(Suppl I):AI l/l. Abstl"act. Maxeiner S, Hansen JB, Nauck M. Switching from a human insulin basal-bohls regimen to insulin analog basal-bolus therapy with insulin detemir/insulin aspart improves glyceiNc control and reduces hypoglycemic episodes in patients with type 1 diabetes: results from German subgroup of the PREDICTIVI~; TM study. 66th Annual Scientific Sessions of the American Diabetes Association; Jm3e 9-13, 2006; Washington, DC. Ruhnall KJ, ttansen JB, Dornhorst A. Switching from basal-bolus therapy with NPH insulin to basM-bolus therapy with the anMog insulin detemir improves glyceiNc control and reduces hypoglycemic episodes, without weight gain in type I and type 2 diabetes patients:
32
Endocrinology and Metabolism Clinics of North America results from German subgroup of the PREDICTIVE sin@. 66th Annual Scientific Sessions of tile American Diabetes Association; June 9-13, 2006; Washington, DC.
* Supplement 1
[40] Roberts A, Standl E, Bayer T, et al. Efficacy and safety of 6-month treatment with insulin deteiNr in type 1 diabetic patients on a basMbolus regimen. Diabetologia 2001;44(Suppl 1):A207. Abstract.