Is there a maximum insulin glargine (Lantus) single-injection dose? Anecdotally, I have heard that patients receiving more than 50 units should split the dose from daily dosing to twice-daily. What’s the evidence?
The question of a maximum insulin glargine dose is not straightforward because it encompasses several issues:
- How long does insulin glargine last? Does it ever need to be given twice-daily?
- Is there a difference in efficacy between daily and twice-daily insulin glargine dosing?
- Can you administer more than 50 units of insulin glargine as one single injection?
Pharmacodynamics and Duration of Insulin Glargine
In theory, insulin glargine should last a full 24 hours without a significant peak effect. Glargine forms a depot effect because it is only soluble at an acidic pH.1 In the vial (pH 4), the drug is completely soluble. Once injected, the solution is neutralized to biologic pH (7.4), which causes the insulin molecules to precipitate. These microprecipitates slowly dissolve over a 24-hour period. This slow dissolution results in a slower onset and a lack of a peak effect compared to other insulins, as shown below:
(Source: DailyMed package insert)
Efficacy of Daily versus Twice-Daily Lantus Administration
Although insulin glargine should last a full 24 hours, there is some evidence that its duration of action may be reduced to 20-23 hours, particularly following injection due to its delayed onset of activity of about 3-5 hours.2 Currently, the best estimate is that 15-30% of type-I diabetics will have pre-injection hyperglycemia and may benefit from twice-daily dosing.
The idea of twice-daily dosing was explored in an 8-week, open-label crossover trial of 20 patients with type-I diabetes.2 Patients received either 100% of a pre-determined dose daily (dinner) or 50% twice-daily (breakfast and dinner). The pertinent results of the trial include:
- The primary endpoint, mean evening blood glucose (prior to evening glargine dose), was not different between daily and twice-daily dosing (155 vs. 133 mg/dL, p=NS)
- The mean 24-hour blood glucose was lower with twice-daily dosing (159 vs. 128 mg/dL, p=0.013)
- There was no difference in hypoglycemic events between the two dosing regimens
Maximum Single-Injection Subcutaneous Dose
Volume Limitations
There is no universally agreed-upon maximum volume for subcutaneous administration. Although one reference suggests a maximum up to 5 mL,3 a maximum of 2-3 mL is likely more reasonable. Because insulin glargine is supplied as 100 units/mL, a volume of 2 mL represents a single-dose of 200 units. Therefore, unless a patient is receiving extremely high doses of glargine (> 200 units), volume is unlikely to be a limitation.
Types of Syringes
There are three volumes of insulin syringes – 3/10 mL (30 units), 1/2 mL (50 units), and 1 mL (100 units). It is possible that the “maximum” of 50 units is derived from the technical limitations of the 1/2 mL syringe.
Lantus SoloStar Pen
The Lantus SoloStar disposable pen has a maximum “dial-able” dose of 80 units. Aside from this technical maximum, there is no mention of a maximum dose in the package insert.1 Because of the mechanics of the pen device, insulin can still be exiting the needle for several seconds after the button is fully depressed. One source recommends waiting 10 seconds when injecting > 50 units to ensure that the entire insulin volume has been delivered, although there is no mention of a total maximum dose.
Maximum Doses are “Expert Opinion” At Best
There does not appear to be a factual basis for maximum insulin glargine doses. With a quick literature and google search, two articles were found, both with different maximum dose recommendations. Not surprisingly, neither article provides a citation supporting the claim of a maximum dose:
- “Volumes greater than 0.5 mL (50 units of U-100 insulin) should be split and injected in separate areas to facilitate absorption” (http://www.aafp.org/afp/2004/0801/p489.html)
- “Because insulin glargine is typically dosed once daily, however, the potential for injecting large doses of insulin (> 90 units) at one site is high, and doing so can lead to poor absorption and decreased efficacy, or lipodystrophy” (https://secure.pharmacytimes.com/lessons/200510-03.asp)
Conclusion
- How long does insulin glargine last? Does it ever need to be given twice-daily?
- In most patients, insulin glargine lasts a full 24 hour period
- In about 15-30% of type-I diabetic patients, twice-daily dosing is appropriate due to a shortened duration of action
- Is there a difference in efficacy between daily and twice-daily insulin glargine dosing?
- In a small trial of type-I diabetics, twice-daily dosing had slightly superior mean glucose values, but the clinical significance of this benefit is unknown. Only a minority of patients demonstrated pre-injection hyperglycemia; therefore, the selection of twice-daily dosing may be appropriate on a case-by-case basis.
- Can you administer more than 50 units of insulin glargine as one single injection?
- Some (unreferenced) articles suggest a maximum of 50-90 units, but there is no evidence supporting this claim
- Lantus SoloStar, a disposable pen, can deliver up to 80 units in a single injection
- The idea of a maximum dose is likely more based on patient preference (eg, injection discomfort, leaking from the injection site) than evidence-based medicine
References
- Insulin glargine [package insert]. Bridgewater, NJ: Sanofi Aventis; 2010. DailyMed link.
- Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart. Diabet Med. 2006;23(8):879-86. PMID 16911626.
- Gomella LG, Haist SA. Chapter 13. Bedside Procedures. In: Gomella LG, Haist SA, eds. Clinician’s Pocket Reference: The Scut Monkey. 11th ed. New York: McGraw-Hill; 2007.
In my particular case (remembering that we are EACH an experiment of one) LANTUS DOES NOT last 24 hours. I have just begun dosing once on awakening and once 12 hours later; hoping that the ‘evening’ dose will become effective and work for me by breakfast. I am a 61 year old male with a 10 year history of Type 2 diabetes controlled variously by diet alone; Metformin alone; and messed up by well-intentioned MD’s trying ‘the latest’ in medications for Type 2 diabetes that did nothing more than screw up my blood glucose levels ROYALLY, to the extend that after the last experiment with new and super medications I am now on LANTUS. And LANTUS alone. I may, at some point, find it necessary to supplement with my Metformin, but I would rather the LANTUS worked on its own to keep my BG “normal”, which to me means small spikes immediately after eating, etc.
Lantus is great, insulin is the most effective product you can use to treat diabetes and I would encourage you to continue Metformin as it has different mechanism of action including reducing the amount of glucose your liver makes. There are proven benefits to metformin and it is a standard of care for all type 2 diabetes patients without contraindication.
This website is the best one I have found for info on lantus. I am very pleased that I finally got the answers I’ve been looking for for years.
is there evidence to support injecting lantus in the evening rather than bedtime or vice versa as kidney pressures may be increased/decreased and therefore support the clearance better? keep hearing this from health care professionals but not seen any clear evidence based information
I’m not aware of any data regarding a difference in clearance throughout the day. I would be shocked if any changes in GFR during the day would actually contribute to a clinically meaningful difference in glycemic control.
The information on this blog is very helpful. I have a patient whose insurance will no longer cover Toujeo. It is difficult to get him to take his insulin and once daily seems to be the only regimen he is willing to try. Since he is on a Toujeo dose of 100 units a day and clearly needs more basal based on AM fastings (180s-200s), can I have him split an equivalent Lantus dose to avoid the volume problem but still dose it once a day? The volume problem is mainly due to the fact that insulin syringes don’t come in larger than 1mL size and he is already at 100 units and needs more. For example can he do 50 units in each thigh once daily instead of 50 units in the morning and 50 units in the evening?
As far as I’m aware, the evidence regarding maximum doses for Toujeo is the same evidence as Lantus. Because Toujeo only comes in pen form, the max dose per injection is dictated by the pen (80 units per injection). With that said, Toujeo does have a longer apparent half-life/duration (but has a slightly reduced glucose lowering effect).