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Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including insulin detemir“, exert their” specific action through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.
Insulin detemir“ is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak.
The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin.
Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 homs after the subcutaneous injection of LEVEMIR or NPH insulin. The mean time between injection and the end of pharmacological effect for insulin detemir” ranged from 7.6 hours to > 24 homs (24 homs was the end of the observation period).
Figure 2: Activity Profiles in Patients with Type 1
Diabetes in a 24-hour Glucose Clamp Study
For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemir exerts more than 50% of its maximum effect from 3 to 4 hours up to approximately 14 hours after dose administration.
Figure 3 shows glucose infusion rate results from a 16-hour glucose clamp study in patients with type 2 diabetes. The clamp study was terminated at 16 hours according to protocol.
Figure 3: Activity Profiles in Patients with Type 2
Diabetes in a 16-hour Glucose Clamp Study
Absorption and Bioavailability
After subcutaneous injection of LEVEMIR in healthy subjects and in patients with diabetes, insulin detemir serum concentrations had a relatively constant concentration/time profile over 24 hours with the maximum serum concentration (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and AUC0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions.
The absolute bioavailability of insulin detemir is approximately 60%.
Distribution and Elimination
More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.
Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours depending on dose.
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children (6-12 years), adolescents (13-17 years), and adults with type 1 diabetes. In children, the insulin detemir plasma area under the curve (AUC) and Cmax were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between adolescents and adults.
Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly ( ≥ 68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance. As with other insulin preparations, LEVEMIR should always be titrated according to individual requirements.
Gender- No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females.
Race- In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were investigated in a clamp study comparing patients with type 2 diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations.
Renal impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-dependent). In this study, there were no differences in the pharmacokinetics of LEVEMIR between healthy subjects and those with renal impairment. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal impairment [see WARNINGS AND PRECAUTIONS].
Hepatic impairment- A single subcutaneous dose of 0.2 Units/kg (1.2 nmol/kg) of LEVEMIR was administered to healthy subjects and those with varying degrees of hepatic impairment (mild, moderate and severe). LEVEMIR exposure as estimated by AUC decreased with increasing degrees of hepatic impairment with a corresponding increase in apparent clearance. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].
Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied [see Use in Specific Populations].
Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied.
Liraglutide -No pharmacokinetic interaction was observed between liraglutide and LEVEMIR when separate subcutaneous injections of LEVEMIR 0.5 Unit/kg (single-dose) and liraglutide 1.8 mg (steady state) were administered in patients with type 2 diabetes.
The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of once-daily or twice-daily NPH insulin in open-label, randomized, parallel studies of 1155 adults with type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2 diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily insulin glargine in an open-label, randomized, parallel study of 320 patients with type 1 diabetes. The evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials that also administered LEVEMIR in the morning. In general, the reduction in glycosylated hemoglobin (HbA1c) with LEVEMIR was similar to that with NPH insulin or insulin glargine.
Type 1 Diabetes – Adult
In a 16-week open-label clinical study (Study A, n=409), adults with type 1 diabetes were randomized to treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 9). Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose (FPG), or body weight.
In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized to twice-daily LEVEMIR (administered in the morning and bedtime) or once-daily insulin glargine (administered at bedtime). Insulin aspart was administered before each meal. LEVEMIR-treated patients had a decrease in HbA1c similar to that of insulin glargine-treated patients.
In a 24-week, open-label clinical study (Study C, n=749), adults with type 1 diabetes were randomized to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on HbA1c.
Table 9: Type 1 Diabetes Mellitus – Adult
|Treatment duration Treatment in combination with||Study A
16 weeks NovoLog® (insulin aspart)
26 weeks NovoLog® (insulin aspart)
24 weeks Human Soluble Insulin (regular insulin)
|Twice-daily LEVEMIR||Twice-daily NPH||Twice-daily LEVEMIR||Once-daily insulin glargine||Once-daily LEVEMIR||Once-daily NPH|
|Number of patients treated||276||133||161||159||492||257|
|Adj. mean change from baseline||-0.8*||-0.7*||-0.6**||-0.5**||-0.1*||0.0*|
|LEVEMIR - NPH||-0.2||-0.0||-0.1|
|95% CI for Treatment difference||(-0.3, -0.0)||(-0.2, 0.2)||(-0.3, 0.0)|
|Basal insulin dose (units/day)|
|Mean change from baseline||16||10||10||4||9||2|
|Total insulin dose (units/day)|
|Mean change from baseline||17||10||9||6||11||3|
|Fasting blood glucose (mg/dL)|
|Adj. mean change from baseline||-44*||-9*||-38**||* * 41 -||-30*||-9*|
|Body weight (kg)|
|Adj.Mean change from baseline||0.2*||0.8*||* * in ©||1.0**||-0.3*||0.3*|
|*From an ANCOVA model adjusted for baseline value and
**From an ANCOVA model adjusted for baseline value and study site.
Type 1 Diabetes – Pediatric
Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6-17 years of age. The other study was 52 weeks in duration and enrolled patients 2-16 years of age. In both studies, LEVEMIR and NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of NPH insulin (Table 10). In the 52-week study, the randomization was stratified by age (2-5 years, n=82, and 6-16 years, n=265) and the mean HbA1c increased in both treatment arms, with similar findings in the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 10).
Table 10: Type 1 Diabetes Mellitus – Pediatric
|Treatment duration Treatment in combination with||Study D 26 weeks NovoLog® (insulin aspart)||Study I 52 weeks NovoLog® (insulin aspart)|
|Once- or Twice Daily LEVEMIR||Once- or Twice Daily NPH||Once- or Twice Daily LEVEMIR||Once- or Twice Daily NPH|
|Number of subjects treated||232||115||177||170|
|Adj. mean change from baseline||-0.7*||-0.8*||0.3**||0.2*|
|LEVEMIR - NPH||0.1||0.1|
|95% CI for Treatment difference||-0.1; 0.3||-0.1; 0.4|
|Basal insulin dose (units/day)|
|Mean change from baseline||8||6||8||7|
|Total insulin dose (units/day)|
|Mean change from baseline||9||7||10||8|
|Fasting blood glucose (mg/dL)|
|Adj. mean change from baseline||-39||-21||-10**||0**|
|Body weight (kg)|
|Adj .Mean change from baseline||1.6*||2.7*||2 7**||3.6**|
|*From an ANCOVA model adjusted for baseline value,
geographical region, gender and age (covariate).
**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratification factor).
Type 2 Diabetes – Adult
In a 24-week, open-label, randomized, clinical study (Study E, n=476), LEVEMIR administered twicedaily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before breakfast and evening) as part of a regimen of stable combination therapy with one or two of the following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase inhibitor. All patients were insulin-na´ve at the time of randomization. LEVEMIR and NPH insulin similarly lowered HbA1c from baseline (Table 11).
In a 22-week, open-label, randomized, clinical study (Study F, n=395) in adults with type 2 diabetes, LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with insulin aspart. As measured by HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.
Table 11: Type 2 Diabetes Mellitus – Adult
|Treatment duration Treatment in combination with||Study E 24 weeks oral agents||Study F 22 weeks insulin aspart|
|Twice-daily LEVEMIR||Twicedaily NPH||Once- or Twice Daily LEVEMIR||Once- or Twice Daily NPH|
|Number of subjects treated||237||239||195||200|
|Adj. mean change from baseline||-2.0*||-2.1*||-0.6**||-0.6**|
|LEVEMIR - NPH||0.1||-0.1|
|95% CI for Treatment difference||(-0.0,0.3)||(-0.2, 0.1)|
|Basal insulin dose (units/day)|
|Mean change from baseline||48||28||26||15|
|Total insulin dose1 (units/day)|
|Mean change from baseline||-||-||57||42|
|Fasting blood glucose2 (mg/dL)|
|Adj. mean change from baseline||-69*||-74*||-||-|
|Body weight (kg)|
|Adj.Mean change from baseline||1.2*||2.8*||0.5**||1.2**|
|1Study E – Conducted in insulin-na´ve patients
2Study F - Fasting blood glucose data not collected
*From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.
**From an ANCOVA model adjusted for baseline value and country.
Combination Therapy with Metformin and Liraglutide
This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on metformin ( ≥ 1500 mg/day) alone or inadequate glycemic control (HbA1c 7-8.5%) on metformin ( ≥ 1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA1c < 7% with liraglutide 1.8 mg and metformin and continued treatment in a nonrandomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions [see ADVERSE REACTIONS]. The remaining 323 patients with HbA1c ≥ 7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and metformin (N=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to addon therapy with LEVEMIR.
Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically significant reductions in HbA1c and FPG compared to continued, unchanged treatment with liraglutide 1.8 mg + metformin alone (Table 12). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8 mg + metformin alone.
Table 12: Results of a 26-week open-label trial of
LEVEMIR as add on to liraglutide + metformin compared to continued treatment
with liraglutide + metformin alone in patients not achieving HbA1c < 7%
after 12 weeks of Metformin and Liraglutide
|LEVEMIR + Liraglutide +Metformin||Liraglutide+ Metformin|
|Intent-to-Treat Population (N)a||162||157|
|HbA1c (%) (Mean)|
|Baseline (week 0)||7.6||7.6|
|Adjusted mean change from baseline||-0.5*||0*|
|Difference from liraglutide + metformin arm (LS mean) b 95% Confidence Interval||-0.5*** (-0.7, -0.4)|
|Percentage of patients achieving A1c < 7%||* * 4||17**|
|Fasting Plasma Glucose (mg/dL) (Mean)|
|Baseline (week 0)||166||159|
|Adjusted mean change from baseline||-38*||-7*|
|Difference from liraglutide + metformin arm (LS mean) b||-31***|
|95% Confidence Interval||(-39 , -23)|
|aIntent-to-treat population using last
observation on study
bLeast squares mean adjusted for baseline value
*From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.
**From a logistic regression model adjusted for baseline HbA1c.
***p-value < 0.0001
A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1 diabetes. [see Use in Specific Populations]
Last reviewed on RxList: 12/2/2013
This monograph has been modified to include the generic and brand name in many instances.
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