Premixed Insulin Analogs: A Case of Patient Selection

The case: Dr George is a retired surgeon. He was first seen 3 years ago at the age of 78 years. He had decided that it was time to take care of himself for a change. His A1C was then 8.5% on maximal therapy with metformin and a sulfonylurea. We spoke about his options and he willingly accepted the recommendation to begin basal insulin therapy to be administered at night in addition to his oral medications. 

Now 3 years later he maintains a reasonable fasting blood sugar (FBS) between 100 to 130 mg/dL but his A1C has returned to 8.5% (having reached 7.2% after the addition of insulin). I explained the need to add prandial insulin to his daily regimen and reviewed the benefits of daily multidose insulin (MDI) therapy. Dr George felt strongly, however, that he wanted a less demanding routine.

Nothing in this scenario is uncommon. Because decline in ß-cell function is progressive hyperglycemia will eventually return despite basal insulin therapy. Resistance like Dr George’s to additional daily injections also is frequently seen.  Thus, the first step in intensifying treatment is to help the patient really understand the options-both pros and cons. Each approach has benefits and weaknesses, which must be weighed against the patient’s lifestyle and willingness. MDI tends to be one of the most effective regimens, but can be too cumbersome for some individuals.  A patient can be eased into MDI treatment, starting with a single prandial injection added to basal insulin therapy and others added as needed over time. Another potential drawback to MDI therapy is the use of multiple insulin pens on a daily basis-we must always acknowledge the potential for confusion between the basal and prandial products-particularly with older patients.  

Is Premixed Insulin an Option?

Patient selection: Use of a premixed insulin product can help ease anxiety for the patient and physician alike-one pen, fewer injections. It’s not appropriate for all patients who require insulin, however. Premixed insulin therapy tends to be most successful for patients who lead a relatively routine lifestyle with three daily meals taken at regular times and with similar carbohydrate content. Examples are older patients with planned mealtimes or patients living in congregate care settings with consistent schedules or some younger persons who may not work or, if they do, have a fixed lunchtime. In the context of a consistent, predictable lifestyle, premixed insulin requires fewer daily injections than MDI therapy and maintains reasonably good glycemic control. The premixed product can be human insulin or analog, and an excellent discussion on this choice can be found in the June issue of Diabetes Care with a debate between Drs George Grunberger and Mayer Davidson.  

In short, both types work but human insulin may be associated with more hypoglycemia, (which can be mitigated by shifting some meal calories to snacks). Analog insulin, although more costly, offers the convenience of meal-time administration, superior postprandial control, and less nocturnal hypoglycemia. I generally use analog premixed with my patients.

Analog MDI vs Premixed Insulin

One of the first trials to document the superiority of twice-daily analog premixed insulin (biphasic insulin aspart 30) over once-daily basal insulin (glargine) was the INITIATE Trial by Raskin, et al. A1C was 0.5% lower with two doses of premixed compared to intensifying the once-daily dose of basal insulin. In essence, the difference was the result of lower postprandial glucose values at breakfast and dinner achieved with the short-acting component of the premixed insulin.

Another comparison of MDI with premixed insulin using analogs was published in the PREFER study by Liebl, et al.  Using only insulin without oral agents MDI showed superiority in this 26-week trial with a 0.23% further reduction in A1C versus the premixed arm. The incidence of minor hypoglycemia was similar in both groups; A1C <7.0% was achieved in 60% of patients in the MDI arm and in 50% of those in the premixed arm. When analyzed by duration of diabetes, the premixed worked very well in patients with less advanced disease.

During my review of available literature, I found several other trials that have looked at the premixed vs basal insulin comparison and, generally, improvement in A1C is of a similar order of magnitude (0.4% to 0.5%) with analog premixed insulin dosed twice daily. In studies where a single prandial injection was added to the basal insulin regimen, the A1C reductions approximated 0.3% to 0.4%. I could find no recent direct comparisons between the two approaches.  An important caveat on comparison of the two formulations is that as doses of prandial insulin (in any form) are added, the risks for hypoglycemia and weight gain are increased versus use of basal insulin therapy alone.

What about Dr George?

I had prescribed Dr George 40 units of a basal analog insulin and instructed him to switch to a premixed insulin analog , taking half (ie, 20 units) at breakfast and half at dinner. The sulfonylurea was stopped, the metformin continued, and he was given an algorithm to follow for increasing the insulin dose. His FBS goal was set at 130 mg/dL in view of his age (78 y) and weekly he would increase the predinner dose by 4 units until the average FBS was at goal. Any hypoglycemia would dictate a reduction in dose. Once the FBS goal was attained, the prebreakfast dose was increased in a similar manner targeting the predinner glucose. I stressed in our discussions the need to eat lunch regularly and to avoid large changes in carbohydrate content from meal to meal. Three months later his A1C was 7.8% and at the six month point it was 7.5%

He was again advised to consider more injections if he wanted to reach the recommended A1C goal of <7%. In my clinical experience, addition of a lunchtime injection of an analog premixed insulin can help further reduce A1C. In a retrospective analysis of my own patients A1C decreased by an additional 0.8% when breakfast and evening doses were reduced and the difference added at lunch. Of course the other option is to convert to true MDI.  Dr George elected not to intensify his treatment.   

In Europe and Asia, a new premixed insulin has been released that incorporates degludec and aspart insulin. Unlike current premixed insulins which require protamination of a rapid analog and use an intermediate type of insulin as the basal component, the components in the new product do not interact at all and so the physiologic profile appears as though one were truly giving two separate injections. The sharper prandial peaks with this combination on a true basal component allow variability in meal timing and a mid-day meal is no longer mandatory to prevent hypoglycemia. Clinical trials have documented a 20% to 30% reduction in nocturnal hypoglycemia compared to current analog premixed insulin.

In conclusion, once insulin therapy is initiated, there are many ways to intensify treatment. Most important is that patient needs to be part of the decision making team. Not every patient will accept or succeed with MDI. Analog premixed insulins are less demanding than MDI and in the appropriate patient are a viable option and can work well.

Take-home Points

Premixed insulin

Benefits: fewer injections, less blood glucose testing, lower overall costs as a result of less testing and the purchase of only one insulin product ( I call this the Chevy with my patients)

Downsides: requires fixed routine and there is a propensity for more hypoglycemia when one deviates from regular scheduled meals

Multidose insulin

Benefits: allows variability in timing of meals as well as in carbohydrate content (This I call the Cadillac)

Downsides: higher maintenance-more glucose testing, more injections, and overall higher costs

For additional information

Comprehensive list of insulins from www.DiabetesinControl.com