Concentrated Insulin in Diabetes Care: Humulin R U-500

Robert Hood, MD: Humulin R U-500 is simply regular Humulin insulin that’s 5-fold concentrated. You’re going to be giving the same number of units in one-fifth of the volume. But when you concentrate regular insulin 5-fold, you do change how it gets absorbed and acts within the body. So Dr de la Peña did an insulin clamp study where they looked at both insulin action and insulin levels. What he found from the insulin action standpoint is that the onset of U-500 insulin is within about 20 minutes, which was no different from U-100 regular insulin.

It shares with U-100 regular insulin this onset that really predicates giving it 30 minutes before a meal and also fulfills the criteria for being mealtime insulin. But unlike U-100 regular insulin, it peaks a little bit later, about 6 hours versus 5 hours, and it can last up to 24 hours. So not only does it provide some mealtime action, but it also has a long duration that makes it suitable for providing some basal insulin. You can give both prandial and basal action with a single injection, and from the patient’s standpoint, it’s a single co-pay.

The initiation titration study was a 24-week, open-label study looking at patients on high doses of U-100 insulin to see what would happen if they were converted to U-500 insulin given either twice daily or 3 times daily. There was a 4-week lead-in period where the U-100 regimens could be adjusted. Insulin secretagogues were stopped during that 4-week lead-in period, but any other oral agent could be continued. They were then randomized to twice-daily or 3-times-daily U-500, and over the ensuing study period, the A1C [glycated hemoglobin] levels dropped by 1.1% with the 3-times-a-day dosing and 1.2% with the twice-a-day dosing. Really, there was no difference in outcomes between the 2 from the standpoint of A1C. Likewise, there was no difference in weight gain or severe hypoglycemia. There were some differences in minor hypoglycemia, with more events occurring with the bid [twice a day] versus the tid [3 times a day] group. The patterns of hypoglycemia in both groups very much mimic the concept that this insulin has both a prandial and basal aspect to it.

During the 4-week lead-in period, some interesting things happened. The total daily dose of insulin went up by about 5% or so, but the A1C dropped by 0.6%. The study effect is very much exaggerated and speaks to the problem with compliance that these patients have with high-dose insulin regimens. At the time of transition, if A1C was 8% or lower, there was a 20% reduction in the total daily dose of insulin.

There was a 38-unit reduction of insulin at the time of transition. It then took them 5 weeks before they got back to the baseline dose, but by 6 weeks, the A1C had already dropped by 0.8%, very suggestive that there’s a compliance issue with these patients. But it’s not too surprising. When you look at the U-100 regimens, the range of insulin injections went anywhere from 2 to 10 injections a day. Imagine asking your patients to take 10 injections of insulin a day. The median number of injections was 5. So here we are taking someone on 5 injections on average and changing them to just 2 or 3 injections of U-500, and lo and behold, you get a nice reduction in A1C.

In the trial, there were also measures of compliance. Both bid and tid U-500 had better measures of compliance versus the U-100 regimen. There was also a measure of injection site pain. The bid and tid U-500 did better than U-100 regimens for injection pain. And from the compliance standpoint, the disease state burden standpoint, bid actually did better than tid.

Serge Jabbour, MD: Based on the product label and based on the FDA, when we switch to U-500, that has to be a type 2 diabetic on more than 200 units of insulin per day. That’s combining basal and mealtime insulin at the same time. When I see those patients, who constitute typically 2% to 5% of all diabetics on insulin, I switch based on the study that was published a few years ago where they took patients on U-100 and switched all the insulins to just U-500. When you switch to U-500, you use it just by itself, and you can do it as 2 injections a day. The way I switch depends on what the A1C is at the time I see those patients. If the A1C is more than 8%, I switch unit per unit. So 100% of the U-100 dose will be switched to U-500. If the A1C is below 8%, I take 80% of the total U-100 insulin dose and use that as the initial U-500 dose. That’s what they did in the landmark study called the Hood study, where they switched patients from U-100 to U-500.

Robert Hood, MD: Historically, U-500 insulin was used for patients who were very insulin resistant. A doctor might feel very comfortable starting it when patients are on 400, 500, or 600 units of insulin a day. But what’s interesting in this trial is that over two-thirds of the patients were taking 300 or fewer units of insulin a day. So from 201 to 300 units. This is not just for patients who are very insulin resistant. Remember, these patients were mostly on basal/bolus insulin therapy. Their A1C was 8.7% at the time of randomization. These are patients not well controlled on conventional therapy. So don’t just think of it with really insanely resistant patients. Again, if over 200 units a day and A1C is not at goal, it’s time to think about U-500 insulin.

Transcript edited for clarity.