Mechanism of Action
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.
Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at neutral pH. At pH 4, as in the LANTUS injection solution, it is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a patient's basal insulin.
In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as human insulin. In euglycemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous insulin glargine was slower than NPH human insulin. The effect profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH human insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.
Figure 1. Activity Profile in Patients with Type 1 Diabetes†
*Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values); indicative of insulin activity.
†Between-patient variability (CV, coefficient of variation); insulin glargine, 84% and NPH, 78%.
The longer duration of action (up to 24 hours) of LANTUS is directly related to its slower rate of absorption and supports once-daily subcutaneous administration. The time course of action of insulins, including LANTUS, may vary between individuals and/or within the same individual.
Absorption and Bioavailability
After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH human insulin. Serum insulin concentrations were thus consistent with the time profile of the pharmacodynamic activity of insulin glargine.
After subcutaneous injection of 0.3 IU/kg insulin glargine in patients with type 1 diabetes, a relatively constant concentration/time profile has been demonstrated. The duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar.
A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.
Age, Race, and Gender
Information on the effect of age, race, and gender on the pharmacokinetics of LANTUS is not available. However, in controlled clinical trials in adults (n=3890) and a controlled clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between insulin glargine and NPH human insulin.
The effect of smoking on the pharmacokinetics/pharmacodynamics of LANTUS has not been studied.
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS has not been studied (see PRECAUTIONS, Pregnancy).
In controlled clinical trials, which included patients with Body Mass Index (BMI) up to and including 49.6 kg/m2, subgroup analyses based on BMI did not show any differences in safety and efficacy between insulin glargine and NPH human insulin.
The effect of renal impairment on the pharmacokinetics of LANTUS has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including LANTUS, may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).
The effect of hepatic impairment on the pharmacokinetics of LANTUS has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including LANTUS, may be necessary in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).
The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH human insulin in open-label, randomized, active-control, parallel studies of 2327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1563 adult patients with type 2 diabetes mellitus (see Tables 1–3). In general, the reduction in glycated hemoglobin (HbA1c) with LANTUS was similar to that with NPH human insulin. The overall rates of hypoglycemia did not differ between patients with diabetes treated to LANTUS compared with NPH human insulin.
Type 1 Diabetes–Adult (see Table 1).
In two large, randomized, controlled clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534) were randomized to basal-bolus treatment with LANTUS once daily at bedtime or to NPH human insulin once or twice daily and treated for 28 weeks. Regular human insulin was administered before each meal. LANTUS was administered at bedtime. NPH human insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily. In one large, randomized, controlled clinical study (Study C), patients with type 1 diabetes (n=619) were treated for 16 weeks with a basal-bolus insulin regimen where insulin lispro was used before each meal. LANTUS was administered once daily at bedtime and NPH human insulin was administered once or twice daily. In these studies, LANTUS and NPH human insulin had a similar effect on glycohemoglobin with a similar overall rate of hypoglycemia.
Table 1: Type 1 Diabetes Mellitus–Adult
| Study A || Study B || Study C |
|Treatment duration||28 weeks||28 weeks||16 weeks|
|Treatment in combination with||Regular insulin||Regular insulin||Insulin lispro|
| LANTUS || NPH || LANTUS || NPH || LANTUS || NPH |
|Number of subjects treated||292||293||264||270||310||309|
| Endstudy mean||8.13||8.07||7.55||7.49||7.53||7.60|
| Adj. mean change from baseline||+0.21||+0.10||-0.16||-0.21||-0.07||-0.08|
| LANTUS – NPH||+0.11||+0.05||+0.01|
| 95% CI for Treatment difference||(-0.03; +0.24)||(-0.08; +0.19)||(-0.11; +0.13)|
|Basal insulin dose|
| Endstudy mean||19.2||22.8||24.8||31.3||23.9||29.2|
| Mean change from baseline||-1.7||-0.3||-4.1||+1.8||-4.5||+0.9|
|Total insulin dose |
| Endstudy mean||46.7||51.7||50.3||54.8||47.4||50.7|
| Mean change from baseline||-1.1||-0.1||+0.3||+3.7||-2.9||+0.3|
|Fasting blood glucose (mg/dL)|
| Endstudy mean||146.3||150.8||147.8||154.4||144.4||161.3|
| Adj. mean change from baseline||-21.1||-16.0||-20.2||-16.9||-29.3||-11.9|
Type 1 Diabetes–Pediatric (see Table 2).
In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. LANTUS was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohemoglobin and the incidence of hypoglycemia were observed in both treatment groups.
Table 2: Type 1 Diabetes Mellitus–Pediatric
|Treatment duration||28 weeks|
|Treatment in combination with||Regular insulin|
| LANTUS || NPH |
|Number of subjects treated||174||175|
| Endstudy mean||8.91||9.18|
| Adj. mean change from baseline||+0.28||+0.27|
| LANTUS – NPH||+0.01|
| 95% CI for Treatment difference||(-0.24; +0.26)|
|Basal insulin dose|
| Endstudy mean||18.2||21.1|
| Mean change from baseline||-1.3||+2.4|
|Total insulin dose|
| Endstudy mean||45.0||46.0|
| Mean change from baseline||+1.9||+3.4|
|Fasting blood glucose (mg/dL)|
| Endstudy mean||171.9||182.7|
| Adj. mean change from baseline||-23.2||-12.2|
Type 2 Diabetes–Adult (see Table 3).
In a large, randomized, controlled clinical study (Study E) (n=570), LANTUS was evaluated for 52 weeks as part of a regimen of combination therapy with insulin and oral antidiabetes agents (a sulfonylurea, metformin, acarbose, or combinations of these drugs). LANTUS administered once daily at bedtime was as effective as NPH human insulin administered once daily at bedtime in reducing glycohemoglobin and fasting glucose. There was a low rate of hypoglycemia that was similar in LANTUS and NPH human insulin treated patients. In a large, randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral antidiabetes agents (n=518), a basal-bolus regimen of LANTUS once daily at bedtime or NPH human insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals as needed. LANTUS had similar effectiveness as either once- or twice-daily NPH human insulin in reducing glycohemoglobin and fasting glucose with a similar incidence of hypoglycemia.
Table 3: Type 2 Diabetes Mellitus–Adult
| Study E || Study F |
|Treatment duration||52 weeks||28 weeks|
|Treatment in combination with||Oral agents||Regular insulin|
| LANTUS || NPH || LANTUS || NPH |
|Number of subjects treated||289||281||259||259|
| Endstudy mean||8.51||8.47||8.14||7.96|
| Adj. mean change from baseline||-0.46||-0.38||-0.41||-0.59|
| LANTUS – NPH||-0.08||+0.17|
| 95% CI for Treatment difference||(-0.28; +0.12)||(-0.00; +0.35)|
|Basal insulin dose|
| Endstudy mean||25.9||23.6||42.9||52.5|
| Mean change from baseline||+11.5||+9.0||-1.2||+7.0|
|Total insulin dose|
| Endstudy mean||25.9||23.6||74.3||80.0|
| Mean change from baseline||+11.5||+9.0||+10.0||+13.1|
|Fasting blood glucose (mg/dL)|
| Endstudy mean||126.9||129.4||141.5||144.5|
| Adj. mean change from baseline||-49.0||-46.3||-23.8||-21.6|
LANTUS Flexible Daily Dosing
The safety and efficacy of LANTUS administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a large, randomized, controlled clinical study, in patients with type 1 diabetes (study G, n=378). Patients were also treated with insulin lispro at mealtime. LANTUS administered at different times of the day resulted in similar reductions in glycated hemoglobin compared to that with bedtime administration (see Table 4). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose level was observed just prior to injection of LANTUS regardless of time of administration, i.e. pre-breakfast, pre-dinner, or bedtime.
In this study, 5% of patients in the LANTUS-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. Routine monitoring during this trial revealed the following mean changes in systolic blood pressure: pre-breakfast group, 1.9 mm Hg; pre-dinner group, 0.7 mm Hg; pre-bedtime group, -2.0 mm Hg.
The safety and efficacy of LANTUS administered pre-breakfast or at bedtime were also evaluated in a large, randomized, active-controlled clinical study (Study H, n=697) in type 2 diabetes patients no longer adequately controlled on oral agent therapy. All patients in this study also received AMARYL® (glimepiride) 3 mg daily. LANTUS given before breakfast was at least as effective in lowering glycated hemoglobin A1c (HbA1c) as LANTUS given at bedtime or NPH human insulin given at bedtime (see Table 4).
Table 4: Flexible LANTUS Daily Dosing in Type 1 (Study G) and Type 2 (Study H) Diabetes Mellitus
|Study G||Study H|
|Treatmentduration||24 weeks||24 weeks|
|Treatment in combination with: ||Insulin lispro||AMARYL® (glimepiride)|
|Number of subjects treated
| Baseline mean||7.56||7.53||7.61||9.13||9.07||9.09|
| Endstudy mean||7.39||7.42||7.57||7.87||8.12||8.27|
| Mean change from baseline||-0.17||-0.11||-0.04||-1.26||-0.95||-0.83|
|Basal insulin dose (IU)|
| Endstudy mean ||27.3||24.6||22.8||40.4||38.5||36.8|
| Mean change from baseline||5.0||1.8||1.5|
|Total insulin dose (IU)||NA
| Endstudy mean||53.3||54.7||51.5|
| Mean change from baseline||1.6||3.0||2.3|