Rapid-Acting Insulin Timing
Health-e-Solutions comment: This article written by Hope Warshaw, MMSc, RD, CDE, BC-ADM, Rapid-Acting Insulin Timing, may help you achieve improved post-prandial glucose control. Blood glucose control is paramount to long term health and avoidance of complications. Understanding the action involved with rapid-acting insulin may be helpful in estimating the correct dose timing.
It’s verging on 20 years since the first rapid-acting insulin, Humalog, was approved by the FDA in the U.S. market. Today we’ve got three, so called, “rapid-acting insulins” approved in the U.S. – Humalog, NovoLog and Apidra. As a clinician who’s been around a long time, I still remember the excitement about finally having a rapid-acting insulin, for which we had the expectation that it would much more closely coincide with the onslaught of glucose from food and blunt the post-prandial rise of glucose (PPG). But with some research, learning from continuous glucose monitoring users (CGM) and lots of practical experience under our belts,
It’s become clear that rapid-acting insulins are, yes more rapid-acting than Regular insulin, but not particularly fast.
When I work with people on an insulin pump or Multiple Daily Injections (MDI) therapy, I take the opportunity to ask “when do you typically take your bolus insulin in relation to when you eat.” The vast majority of people say, “when I sit down to eat” or “when I know what I’m going to eat.” Others say, “after I eat, when I know how much food I ate.” These are quite understandable responses for several reasons:
1) It’s what they’ve likely been taught about rapid-acting insulin,
2) It reflects the concern for safety/prevention of hypoglycemia,
3) It reflects the practical issues regarding food intake and carb counting (it’s way harder to execute than we, as clinicians, portray!)
I take these opportunities to share the research and offer practical pointers to safely use rapid-acting insulin, while hopefully helping people achieve improved post-prandial glucose control.
To flesh out this discussion and widen the perspective, I’ve sought the input of two colleagues well versed in intensive diabetes management, Alison Evert, MS, RD, CDE, Coordinator of Diabetes Education Programs at University of Washington Medical Center, Diabetes Care Center and co-editor of ADA’s Guide to Nutrition Therapy for Diabetes and Gary Scheiner, MS, CDE, owner of Integrated Diabetes Services in Wynnewood, PA, and author of Think Like a Pancreas, 2nd ed (DeCapo) and Until There Is A Cure (Spry Publishing).
The Real Action Curve of Rapid-Acting Insulin?
As noted, when rapid-acting insulin first entered our armamentarium, clinicians erred on the side of caution and encouraged people to take it just before eating the first bites of food or after eating. In retrospect, we might have over reacted to the speed of its action in relation to Regular insulin. The insulin action times of the available rapid-acting insulins (analogs) are provided by manufacturers as roughly: onset 5 to 15 minutes, peak between 30 to 90 minutes and duration of action about 4 to 6 hours.1 In the book Pumping Insulin , 5th ed, authored by Walsh and Roberts, the authors differentiate the action time of rapid-acting insulin with duration of insulin action. They define insulin action time as “[when] researchers give people without diabetes an injection of insulin and then measure the duration and amount of glucose that needs to be infused from an IV…to keep glucose flat at 90mg/dl.”Duration of insulin action is defined as: “time measured from when a pump bolus is given to the end of the insulin action [from that bolus] while a basal dose is still being delivered.”2 Walsh and Roberts note that, the pharmodynamic times (as noted above) underestimate the duration of insulin action.
In Scheiner’s usual blunt and to the point style, he says, “I think it’s libelous to call these insulins “rapid-acting”. Yes, more rapid than Regular insulin, but WAAAY slower than the insulin secreted by a functioning pancreas.”
Since the approval of rapid-acting insulins, clinicians, through some research and lots of observations, have learned that to adequately blunt the PPG rise, it’s important to create a “lag time” with these insulins – defined as the amount of time that needs to elapse between the prandial injection and a meal.1
Small Bits of Relevant Research
Recently, Evert, in an effort to provide evidence-based practice, notes she “went looking for actual research that had been conducted to support the clinical experience-based recommendations she and her colleagues were giving about rapid-acting insulin timing.” The fruits of Evert’s labor are now published.1 She recaps the research as follows: There are very few studies. The few available studies used small numbers of subjects. With these studies, the timing of the pre-meal insulin DID matter.
Most of the studies concluded with the recommendation to administer the rapid-acting injection or bolus dose 15 to 20 minutes BEFORE eating to more closely match the insulin dose with the quick rise of glucose from food intake.
This effort, Evert’s research shows, “can really help to reduce glycemic variability.” However, Evert concludes, “we can’t just cavalierly offer this recommendation. Clinical judgment and individualization remain paramount.”
Learnings from CGM and Artificial Pancreas Research
Clinicians have and are learning more about the action curve of rapid-acting insulin from people using CGM and CGM research. Evert notes, she and her colleagues have a lot of people using CGM. “People using this technology witness, in real-time, PPG levels that start to rise immediately after the intake of calorie-containing foods or beverages.”
These observations help people see first-hand that they need to give their rapid-acting insulin a head start when possible.
Scheiner adds, “CGM is the best tool for evaluating PPG. It captures both the magnitude and timing of the “peak”.
We’ve learned that the majority of foods we eat raise the blood sugar faster than rapid-acting insulin lowers it. On the converse, though, CGM also shows us how slow-digesting foods can produce flatter post-meal blood sugar patterns.”
The work on artificial pancreas systems are also helping us learn more about the action curve of rapid-acting insulins. The study by the research team of Russell and Damiano from Boston who are pursuing a bi-hormonal model, showed a large inter-subject and intra-subject variation in the peak of rapid-acting insulin (Iispro) action from 24 to 166 minutes (mean 70 ± 40 minutes).4 Their results also showed that the use of a meal-priming bolus (as part of the artificial pancreas system) helped control post-prandial glucose levels. This teaches us that a one-size-fits-all approach with rapid-acting insulin is not sufficient. As this research proceeds we’ll amass more learning.
Is Faster-Acting Insulin On the Horizon?
Research and development to bring faster-acting insulins to market is going on fast and furious, but Scheiner estimates, we’re still a ways off from having it.”
This brief update is in the chronological order these insulins may come to market.
- Halozyme is a company working on the concept of delivering a “pre-administration” solution of the enzyme (PH20). One of their products is Hylenex, which would be pre-administered by pump users prior to insertion of an infusion set. The other is a co-formulation of PH20 and rapid-acting insulin. The addition of the PH20 enzyme temporarily degrades connective tissue in the skin, allowing insulin to be absorbed more quickly. Phase 4 studies are expected to begin this year on Hylenex with potential approval in 2014. This concept is already approved to speed the delivery of other subcutaneously delivered drugs.
- Mannkind’s Afrezza is an ultra-rapid-acting mealtime insulin which is delivered via inhalation with a small hand-held device. Afrezza has experienced a rocky regulatory path to date at FDA. At this point FDA approval, if it happens, could be early in 2014.
- An ultra-rapid acting formulation of Novolog (insulin aspart), called NN1218, is expected to progress to a 3,000 person phase 3 study late in 2013 with a broad estimate of approval, if all goes well, in 2015-16.
- Biodel is a company with several ultra-rapid-acting insulins in research and development. BIOD-123 is recombinant ultra-rapid-acting human insulin. BIOD-238 and 250 are analog-based ultra-rapid-acting insulins. All are still relatively early in the development process.
- A couple of devices to more quickly deliver rapid-acting insulin are also being investigated. One is from BD which would use microneedles to deliver insulin intradermally. Then there’s a company called InsuLine which is developing InsuPad, which would be used to warm an injection site to speed the absorption of rapid-acting insulin for those on MDI.
Beyond being a huge value to people using pumps or MDI, the availability of ultra-rapid-acting insulin would be a big plus to researchers working on artificial pancreas systems, because it would make it easier to tightly control glucose levels using their algorithms.
To the Practical Pointers
Let’s get practical, as long as we have to work with rapid-acting insulin for at least a few more years.
Scheiner who discusses the timing of boluses in his book, Think Like a Pancreas, notes, “A properly timed bolus in the proper quantity…now that’s a thing of beauty.”3
In clinical practice, Scheiner says, “Before giving any recommendations, I like to first see if there’s a current problem, such as if the PPGs are peaking too high and therefore changing the timing of mealtime insulin will be important.” He suggests, “this can be determined by using a CGM or by checking glucose an hour after eating for a week or so. If glucose levels are peaking above target consistently, then suggest a person takes their pre-meal bolus 15-30 minutes before hand to help blunt that rise. For some people, they only need to do this for one meal, such as breakfast. “But for pumpers, do be sure that they’re not trying to fix with bolus timing or the amount of bolus insulin what they should be fixing with a basal dose adjustment. To help a client practically implement creating lag time for bolus dosing, help them think through their current routine and how they might be able to adjust this to take the bolus a bit earlier. For example, suggests Scheiner, ” Let’s say a person normally wakes up, gets ready for the day, then gives their bolus dose, then eats breakfast. Ask them if they can reorder their routine to take the insulin right after they get up. Or, if they usually have lunch at noon, set an alarm on their meter or use a bolus reminder on their pump to take their lunch time bolus at 11:40 am.”
At UWMC Diabetes Care Center, Evert says they often suggest clients use an easy-to-remember formula for pre-meal bolus insulin, “if a glucose result is in the 100s – wait [to eat] 10 minutes, in the 200s – wait 20 minutes, if over 300 mg/dL – wait 30 minutes.” No doubt this has practical challenges in everyday life, but the more it can be practiced, the better glucose control is likely. Evert included a table with similar recommendations – albeit a bit more formal – in her publication.1
However, Evert alerts us to not assume that everyone is aware of the action curve of rapid-acting insulin. “We still have clients who have recently switched from Regular insulin to a rapid-acting insulin analog or from a pre-mixed insulin pen to an MDI routine.” It’s essential to review the action curve of rapid-acting insulin in comparison to the slower acting insulin they were on and offer advice about the optimal times to take it and the potential for hypoglycemia.
She says, “I always encourage safety first. If a person is eating at home and consuming a known amount of carbohydrates, they should try to take their pre-meal bolus with their “lag-time” factored in. However, if they are at all uncertain, such as in a restaurant, especially a new restaurant, when they know the food will be just a bite or two away, take the insulin when you have food in front of you or know for sure it’s close by.”
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- Evert AB. Nutrition Therapy for Adults with Type 1 and Insulin Requiring Type 2 Diabetes. In: Evert A, Franz M: Diabetes Nutrition Therapy, American Diabetes Association, 2012.
- Walsh, J, Roberts R: Pumping Insulin, 5th ed. Torrey Pines Press. 2012
- Scheiner, G: Think Like A Pancreas, 2nd ed. DaCapo. 2011.
- Russell S: Blood Glucose Control in Type 1 Diabetes With a Bihormonal Bionic Endocrine Pancreas. Diabetes Care. 2012; 35:2148-2155.