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Weight gain can be a significant barrier to the treatment of diabetes. Insulin detemir is a basal insulin analog that can help patients move safely toward glycemic targets with less weight gain. This review discusses the potential adverse effects of, and hypothesis for, weight gain resulting from intensive insulin management of diabetes. In addition, an assessment of all weight change data from clinical trials and observational studies involving insulin detemir are presented. Finally, we discuss how the ability of insulin detemir to closely mimic endogenous insulin secretion leads to more predictable glycemic control with reduced weight gain and provides patients with a more acceptable method of achieving glycemic control.
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PMID:Intensive diabetes therapy and body weight: focus on insulin detemir. 1788 30

The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation 303 (PREDICTIVE 303) Study (n = 5604) evaluated the effectiveness of insulin detemir, a long-acting basal insulin analogue, using a simplified patient self-adjusted dosing algorithm (303 Algorithm group) compared with standard-of-care physician-driven adjustments (Standard-of-care group) in a predominantly primary care setting, over a period of 6 months. Insulin detemir was to be started once-daily as add-on therapy to any other glucose-lowering regimens or as a replacement of prestudy basal insulin in patients with type 2 diabetes. Investigator sites rather than individual patients were randomized to either the 303 Algorithm group or the Standard-of-care group. Patients from the 303 Algorithm group sites were instructed to adjust their insulin detemir dose every 3 days based on the mean of three 'adjusted' fasting plasma glucose (aFPG) values (capillary blood glucose calibrated to equivalent plasma glucose values) using a simple algorithm: mean aFPG < 80 mg/dl (<4.4 mmol/l), reduce dose by 3 U; aFPG between 80 and 110 mg/dl (4.4-6.1 mmol/l), no change; and aFPG > 110 mg/dl (>1.1 mmol/l), increase dose by 3 U. The insulin detemir dose for patients in the Standard-of-care group was adjusted by the investigator according to the standard of care. Mean A1C decreased from 8.5% at baseline to 7.9% at 26 weeks for the 303 Algorithm group and from 8.5 to 8.0% for the Standard-of-care group (p = 0.0106 for difference in A1C reduction between the two groups). Mean FPG values decreased from 175 mg/dl (9.7 mmol/l) at baseline to 141 mg/dl (7.8 mmol/l) for the 303 Algorithm group and decreased from 174 mg/dl (9.7 mmol/l) to 152 mg/dl (8.4 mmol/l) for the Standard-of-care group (p < 0.0001 for difference in FPG reduction between the two groups). Mean body weight remained the same at 26 weeks in both groups (change from baseline 0.1 and -0.2 kg for the 303 Algorithm group and the Standard-of-care group respectively). At 26 weeks, 91% of the patients in the 303 Algorithm group and 85% of the patients in the Standard-of-care group remained on once-daily insulin detemir administration. The rates of overall hypoglycaemia (events/patient/year) decreased significantly from baseline in both groups [from 9.05 to 6.44 for the 303 Algorithm group (p = 0.0039) and from 9.53 to 4.95 for the Standard-of-care group (p < 0.0001)]. Major hypoglycaemic events were rare in both groups (0.26 events/patient/year for the 303 Algorithm group and 0.20 events/patient/year for the Standard-of-care group; p = 0.2395). In conclusion, patients in the 303 Algorithm group achieved comparable glycaemic control with higher rate of hypoglycaemia as compared with patients in the Standard-of-care group, possibly because of more aggressive insulin dose adjustments. The vast majority of the patients in both groups were effectively treated with once-daily insulin detemir therapy. The use of insulin detemir in this predominantly primary care setting achieved significant improvements in glycaemic control with minimal risk of hypoglycaemia and no weight gain.
Diabetes Obes Metab 2007 Nov
PMID:The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes--results of the randomized, controlled PREDICTIVE 303 study. 1851 25

Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.
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PMID:Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. 1858 81

Insulin detemir (detemir) has previously been shown to be associated with lower within-subject variability compared with other basal insulin preparations in adults with type 1 diabetes mellitus (T1DM). This randomized, double-blind, crossover trial compared the within-subject variability of detemir and insulin glargine (glargine) in pharmacokinetic properties in children and adolescents with T1DM. The trial enrolled 32 children and adolescents (19 girls and 13 boys; mean +/- SD: age 13 +/- 2.5 yr and T1DM duration 6.3 +/- 3.0 yr) with a hemoglobin A1c (HbA1c) of 7.9 +/- 1.0%. Participants were randomized to a specific treatment sequence in which a dose of 0.4 U/kg of detemir and glargine was injected subcutaneously 24 h apart at each of two dosing visits. Insulin concentrations were measured at frequent intervals for a period of 16-h post-dosing. Detemir showed statistically significantly less within-subject variability compared with glargine with a 3.1-fold and 2.9-fold lower coefficient of variation (CV, %) for the area under the concentration-time curve [AUC((0-16) (h))] and the maximum concentration (C(max)), respectively. Separate analyses demonstrated a 2.5-fold and 2.9-fold lower CV (%) with detemir in children (8-12 yr) and a 4-fold and 3.8-fold lower CV (%) with detemir in adolescents (13-17 yr). No safety concerns were raised during the trial. In conclusion, within-subject variability in pharmacokinetic properties was significantly lower for detemir than for glargine in children and adolescents with T1DM. This indicates a less variable absorption with detemir, which is expected to be associated with a more predictable therapeutic effect also in this population.
Pediatr Diabetes 2008 Dec
PMID:Insulin detemir is characterized by a more reproducible pharmacokinetic profile than insulin glargine in children and adolescents with type 1 diabetes: results from a randomized, double-blind, controlled trial. 1876 44

Once-daily dosing with insulin detemir and insulin glargine were compared in a double-blind, randomised, crossover study in type 2 diabetes subjects previously treated with other antihyperglycaemic medications. Blood glucose was measured through continuous glucose monitoring (CGM). Insulin dose was adjusted daily during the titration phase to achieve target blood glucose values of (70-120 mg/dL) during the basal period, defined as 2400-0600 hours. The last meal of the day started at 1800 h and basal insulin was injected at 2000 h. The CGM data for a 24-h period on the second consecutive day after achieving target blood glucose levels were compared between treatments. Twenty-nine subjects completed the study. Over a 24-h measurement period, once-daily dosing with insulin detemir provided glycaemic control very similar to that of once-daily insulin glargine in patients with type 2 diabetes after both had been titrated to the same glucose target. Insulin detemir- and insulin glargine-treated subjects had similar mean 24-h glucose values (133 +/- 21 mg/dL compared with 126+/-20 mg/dL respectively, p = 0.385) and similar glucose values during the basal period (105 +/- 23 mg/dL compared with 98 +/- 19 mg/dL, respectively p = 0.204).Target basal glycaemic control was achieved in all subjects in a mean of 3.8 days for detemir and 3.5 days for glargine (p = 0.360). The mean dose of detemir was similar to that of glargine (26.3 and 26.6 units/day, respectively, p = 0.837). In this study, once-daily dosing of insulin detemir provided 24-h glycaemic control similar to that of insulin glargine in patients with type 2 diabetes.
Diabetes Obes Metab 2009 Jan
PMID:Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study. 1912 Apr 33

Basal insulin analogues are an effective treatment for type 2 diabetes with proven efficacy, and insulins NPH, detemir and glargine have shown comparable glycaemic control. However, pharmacokinetics and clinical studies highlight the advantages of insulins detemir and glargine over insulin NPH in terms of once-daily dosing, reduced risk of hypoglycaemia, reduced within-patient variability, appropriate duration of action and simple titration. Insulin detemir has demonstrated the additional advantage of less weight gain. Introduction of insulin detemir, at the appropriate time, can help empower patients to reach glycaemic targets, with a reduced risk of hypoglycaemia and less weight gain.
Prim Care Diabetes 2010 Apr
PMID:Basal insulins: Pharmacological properties and patient perspectives. 2039 87

Diabetes has become the tsunami of non-communicable chronic diseases, with its alarmingly high prevalence largely driven by the global obesity epidemic. Achieving a healthy weight and preventing weight gain are integral components of optimal diabetes management. A modest weight loss of 5-10% is associated with significant reduction in blood sugar, lipid and blood pressure levels. Insulin detemir is an effective basal insulin analogue associated with less weight gain compared with both insulin NPH and insulin glargine. Once-daily insulin detemir could be considered an effective therapy for people with type 2 diabetes on lifestyle interventions and oral anti-diabetic agent therapy who require insulin.
Prim Care Diabetes 2010 Apr
PMID:Diabetes and weight management. 2039 88

Insulin detemir provides prolonged, reproducible blood glucose reduction through a mechanism unique among basal insulins. It was originally studied clinically in predominantly basal + bolus regimens and found to be associated with a low risk of hypoglycaemia compared to insulin NPH, and reduced weight gain compared to other basal insulins. Insulin detemir has been increasingly studied in basal-only insulin regimens in type 2 diabetes, in which an understanding of how to optimize its use has been built incrementally. Glycaemic control and limitation of weight gain tend to be maximized by once-daily (evening) dosing, earlier initiation and careful titration to appropriate fasting glucose targets.
Prim Care Diabetes 2010 Apr
PMID:Insulin detemir: A historical perspective on a modern basal insulin analogue. 2039 90

While evidenced-based guidelines promote glycated hemoglobin (HbA(1c)) targets <7.0% in order to reduce the long-term risk of diabetic complications, many individuals with type 2 diabetes do not achieve these targets. Fear of hypoglycemia provides a major barrier to improving blood glucose control as a result of delayed insulin initiation and failure to appropriately titrate insulin following initiation. Modern insulin analogs were designed to achieve improved blood glucose control with similar hypoglycemic risk compared with non-analog insulins (or similar blood glucose control with reduced hypoglycemic risk). While this has been demonstrated in randomized controlled trials, there is a need to confirm these findings in an everyday clinical setting. The A(1)chieve study will evaluate adverse events and effectiveness of premix (biphasic insulin aspart 30 [NovoMix 30]), basal (insulin detemir [Levemir]), and meal-time (insulin aspart [NovoRapid]) insulin analogs in people with type 2 diabetes in near-routine clinical practice. A(1)chieve is an international, prospective, multi-center, open-label, non-interventional, 24-week study of people with type 2 diabetes using an insulin analog. The study will recruit 60 000 people from 30 countries across four continents (Asia, Africa, South America, and Europe). The primary aim of the study is to assess the adverse event profile of the study insulins in routine clinical practice, including rates of hypoglycemia. In addition, effectiveness (HbA(1c), fasting plasma glucose, and postprandial plasma glucose) and patient quality of life outcomes will be measured. Comprehensive epidemiological data will be collected at baseline, including recent plasma glucose results and hypoglycemic episodes, prevalence of diabetes-related complications, and measures of current standards of care. Thus, A(1)chieve should provide important information about how insulin analogs perform in daily clinical practice.
Diabetes Res Clin Pract 2010 May
PMID:The A1chieve study: a 60 000-person, global, prospective, observational study of basal, meal-time, and biphasic insulin analogs in daily clinical practice. 2046 63

Basal insulin analogs are used to minimize unpredictable processes of NPH insulin. Modification of the human insulin molecule results in a slower distribution to peripheral target tissues, a longer duration of action with stable concentrations and thus a lower rate of hypoglycemia. Insulin detemir is a basal insulin analog that provides effective therapeutic options for patients with type 1 and type 2 diabetes. For glycemic control, no significant differences were found in HbA1c levels compared with NPH and insulin glargine. It is comparable with insulin glargine in significantly reducing rates of all types of hypoglycemia. Clinical studies have demonstrated that detemir is responsible for significantly lower within-subject variability and no or less weight gain than NPH insulin and glargine. Recent pharmacodynamic studies have shown that detemir can be used once daily in many patients with diabetes. Together with patient-friendly injection devices and dose adjustments, it provides a treatment option with the potential to lower the key barriers of adherence to insulin therapy in type 2 diabetes. Recent guidelines for treatment of type 2 diabetes suggest starting intensive therapy of hyperglycemia at an early stage of diabetes and recommend therapeutic options that provide the possibility of reaching HbA1c goals individually, with a low risk of hypoglycemia or other adverse effects of treatment. The properties of insulin detemir match these requirements.
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PMID:An update on the treatment of type 1 and type 2 diabetes mellitus: focus on insulin detemir, a long-acting human insulin analog. 2053 42


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