Insulin therapy in type 2 diabetes mellitus -Combining prandial and basal insulin

Combining prandial and basal insulin — For patients with type 2 diabetes who require prandial insulin, the goal is to adjust the dose of short-acting or rapid-acting insulin immediately prior to a meal, and therefore, we prefer to keep basal and pre-meal insulin injections separate and adjust them independently. Patients may draw up their pre-meal and NPH insulin in the same syringe prior to injection, whereas glargine, degludec, and detemir cannot be mixed with rapid-acting insulin.

●Choice of prandial insulin – The choice of prandial insulin is based upon availability, patient preference, cost, and payer coverage. The newer rapid-acting insulins have a minor glycemic advantage and the convenience of administration timing closer to the meal over regular insulin in patients with type 1 diabetes, but they do not have a clinically significant advantage in patients with type 2 diabetes [41,42]. This was illustrated in a meta-analysis of 10 randomized trials (involving 2751 patients with type 2 diabetes) that compared rapid-acting insulin analogs with regular insulin as pre-meal bolus doses [42]. No significant differences were seen in serum A1C concentrations or the number of hypoglycemic episodes. However, the ability to inject the rapid-acting insulins immediately before meals (as opposed to the 30 to 45 minutes before the meal recommended for short-acting insulins) may provide improved convenience for patients.

●Pre-meal insulin dosing – The optimal dose of pre-meal insulin depends upon many factors, including current and target blood glucose values, carbohydrate content of the meal, and activity. A typical starting dose is approximately 4 to 6 units (algorithm 1). The dose can be increased by 2 to 3 units every three days until the postprandial blood glucose target is achieved.

A more complex method for adjusting pre-meal insulin is to match insulin delivery to the anticipated glucose excursion with meals. Many patients benefit from specific training in carbohydrate counting, which requires some arithmetical computations that some patients find difficult or burdensome. It is uncertain if there is a glycemic advantage to carbohydrate counting in patients with type 2 diabetes. As an example, in a 24-week, randomized trial in 277 adults with type 2 diabetes, there was no difference in A1C values when mealtime insulin adjustments were based upon a simple algorithm (according to previous weeks' blood glucose monitoring results) versus carbohydrate counting, using an insulin-to-carbohydrate ratio for each meal [43]. Either method is acceptable, and patient preference can guide the choice of method for pre-meal dosing. A simplified adaptation in which patients take a slightly higher dose of prandial insulin for high carbohydrate meals may yield many of the benefits of carbohydrate counting without the complexity and is more straightforward for most patients with type 2 diabetes. (See "Nutritional considerations in type 2 diabetes mellitus", section on 'Carbohydrate consistency'.)

●Pre-mixed insulin – Some insulins are commercially available in a pre-mixed formulation. Most pre-mixed (biphasic) preparations contain an intermediate-acting insulin and either a short-acting or a rapid-acting insulin. We suggest not using pre-mixed insulin initially, because of limited flexibility in adjusting doses. However, pre-mixed insulin is a reasonable option for patients with type 2 diabetes who are doing well on a stable, fixed ratio, particularly those who eat a larger breakfast and dinner and a smaller lunch. (See "General principles of insulin therapy in diabetes mellitus", section on 'Pre-mixed insulins'.)

Pre-mixed rapid-acting preparations offer little glycemic advantage compared with adequately titrated basal and bolus insulin. In an open-label trial, 708 patients with type 2 diabetes who were suboptimally controlled with metformin and a sulfonylurea were randomly assigned to pre-mixed biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily), there was no difference in median A1C levels among the three groups (7.1, 6.8, and 6.9 percent, respectively), but significantly more patients in the basal and prandial groups achieved an A1C level ≤6.5 percent than in the pre-mixed biphasic group (43, 45, and 32 percent, respectively) [21]. The majority of all three treatment groups used a second type of insulin, per protocol, during the trial to obtain the stipulated glycemic goals. Patients in the basal group had the fewest episodes of hypoglycemia. In other trials, pre-mixed rapid-acting preparations were more often associated with minor hypoglycemia and weight gain than long-acting insulin or oral agents [44].

●Intensive insulin regimens – If intensive insulin therapy is chosen in a patient with type 2 diabetes, the pretreatment considerations, choice of regimen, and management issues are similar to those for patients with type 1 diabetes. Insulin pump therapy is used infrequently in patients with type 2 diabetes, but it may have a role in a select group of patients with poorly controlled type 2 diabetes taking multiple daily injections [45]. In a short-term trial comparing an automated closed-loop insulin delivery system with conventional subcutaneous insulin therapy in hospitalized patients (noncritical care) with type 2 diabetes, a greater proportion of patients receiving pump therapy were in the target range of 100 to 180 mg/dL (5.6 to 10 mmol/L; 65.8 versus 41.5 percent) [46]. However, the mean glucose level was within target range for hospitalized patients in both groups (154 versus 188 mg/dL in the control group [8.5 and 10.4 mmol/L]), and there was no significant difference in duration of hypoglycemia or in the amount of insulin delivered. Whether the modest improvement in glycemic control in noncritical hospitalized patients improves outcomes and is merited, considering the potential increased cost, remains to be demonstrated. Intensive insulin therapy is reviewed in detail elsewhere. (See "Management of blood glucose in adults with type 1 diabetes mellitus".)

Use of an intensive insulin regimen (similar to that used in type 1 diabetes) results in higher serum insulin concentrations and better glycemic control than that achieved with either an oral drug or conventional insulin therapy alone [47]. A potential problem is the weight gain (averaging 8.7 kg in one study) that can occur with intensive regimens that achieve near-normoglycemia [48]. This weight gain may, in some instances, result in partial noncompliance with therapy, particularly in women. (See 'Disadvantages' above and "Nutritional considerations in type 2 diabetes mellitus".)