Commentary by Kathy Lee, Pharmacy Resident
The goal of diabetes management is to reduce the risk of long-term complications by maintaining near-normal glycemic control, in addition to reducing other risk factors. Patients with type 1 diabetes have an absolute deficiency in insulin and require exogenous insulin replacement. Lantus®, human insulin analog glargine, is the only long-acting insulin that exhibits a “peakless” action profile with duration of action of up to 24 hours(1). Because the clinical trials demonstrating its safety and efficacy involved a once a day bedtime administration, Lantus® received a FDA indication for once-daily dosing for diabetic patients who require basal insulin.
Theoretically, since insulin glargine has a 24-hour action profile with no pronounced peak, the time of administration should not be significant. A 24-week randomized clinical trial(2) investigated this idea by comparing administration of glargine at breakfast, dinner, or bedtime in patients with type 1 diabetes. The study concluded that the efficacy and safety of insulin glargine was not affected by the timing of administration. Despite limited studies there have been some evidence implying the appropriateness of twice-daily insulin glargine in select type 1 diabetic patients.
In August 2002, a patient case regarding the use of twice-daily insulin glargine was published(3). In this case, a 53 year old male with a history of type 1 diabetes did not receive sufficient insulin coverage with a once daily injection. Before hospitalization, the patient had a history of widely variable blood glucose levels. He was on a 4-injection regimen of premeal insulin lispro and ultralente at dinner. The patient also had a history of heavy alcohol abuse and on admission, the patient developed left arm weakness and progressive loss of consciousness. He was diagnosed with compensated diabetic ketoacidosis, and after treatment, was maintained on IV insulin infusion between 1-2 units/h. On the fifth day of his hospital course, the patient was started on enteral feeding with total nutrition intake of 1680 kcal/day. He was then later given 30-unit dose of insulin glargine at 9:00 p.m. and was weaned off of the insulin infusion over the next 4 hours. From day 6 to day 12 (period 1), the patient received insulin glargine as a single dose. In addition, he received subcutaneous insulin lispro when glucose exceeded 200 mg/dl. Marked hyperglycemia was noted at 10:00 p.m. after the single-dose regimen, requiring that the patient receive a supplemental lispro injection 4 out of the 6 days. From days 13-18 (period 2), glargine was divided into two doses, administered at 9:00 a.m. and 9:00 p.m. The mean glucose level was significantly higher at 10:00 p.m. in treatment period 1 versus period 2. This data suggested that the slow onset of action for the subsequent nighttime dose resulted in higher blood glucose levels at night. Giving insulin glargine as a split dose every 12 hours eliminated the window of insulinopenia and provided effective 24 hour insulin coverage.
Additionally, an 8-week, randomized, cross-over study compared once-daily and twice-daily administration of insulin glargine in Type 1 diabetic patients(4). This study was based on previous pharmacokinetic studies demonstrating a less than 24-hour duration of action in some patients. In this trial, 20 Type 1 diabetic patients were randomized to receive a once-daily at dinner time injection of insulin glargine or twice-daily injections at breakfast and dinner time. Both groups received insulin aspart injections at meals. Patients were asked to perform an eight point 24-hour self-monitored blood glucose (SBMG) profile once in the week prior to each study visit and to measure pre-breakfast SMBG concentration daily. Study visits occurred weekly and at each consultation, SMBG levels, hypoglycemia, and insulin doses were reviewed. At the end of each 4-week period, patients were admitted for a 24-hour inpatient metabolic profile. Daily insulin dose did not differ between twice-daily and once-daily glargine. Results of this study are as follows: once-daily glargine resulted in higher glucose concentrations through the afternoon, while glucose concentrations remained stable with twice-daily glargine. Mean 24-hour SMBG concentrations and within day variability was lower with twice-daily glargine (p = 0.031 and p = 0.044, respectively). Plasma free insulin concentration was higher 3 hours after lunch, but lower 2 hours after dinner in twice-daily compared to once-daily. There was no statistical significance in the number of reported hypoglycemic episodes between both groups.
This study confirmed that in some people with Type 1 diabetes, the duration of action of once-daily insulin glargine is not sufficient to provide optimal glycemic control around the clock. The pre-injection hyperglycemia exhibited by some patients was prevented by twice-daily insulin glargine. This was suggested to be a result of the waning insulin levels in the period approaching 24 hours after injection in combination with a delay of 3-5 hours from injection until plateau of metabolic effect(1,4). However, only a minority of people suffer from pre-injection hyperglycemia with insulin glargine. In this study, significant late-afternoon hyperglycemia with once-daily administration was seen in 15% of the participants. While twice-daily insulin glargine reduced the hyperglycemia by 4.9 mmol/l in this group, no other benefits were seen. Thus, once-daily glargine is sufficient for the majority of Type 1 diabetic patients, however, there are exceptions in which twice-daily injection is appropriate.
1. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000;49:2142-2148.
2. Hamann A, Matthaei S, Rosak C, Silvestre L. A randomized clinical trial comparing breakfast, dinner, or bedtime administration of insulin glargine in patients with Type I diabetes. Diabetes Care 2003;26:1738-1477
3. Clement S, Bowen-Wright H. Twenty-four hour action of insulin glargine (Lantus) may be too short for once-daily dosing: A case report. Diabetes Care 2002;25:1479-1480.
4. Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with Type I diabetes using meal-time insulin aspart. Diabet Med 2006;23:879-886.
5. Triplitt CL, Reasner CA, Isley WL. Diabetes Mellitus. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill; 2005:1333.