Steve V. Edelman, MD
Robert R. Henry, MD
One of the more common insulin regimens utilized in Type 2 diabetes mellitus is a split-mixed regimen consisting of a prebreakfast and predinner dose of an intermediate- and a fast-acting insulin. This split-mixed regimen of two injections per day is often inadequate for patients with Type 1 diabetes mellitus and results in persistent…
early morning hypoglycemia and fasting hyperglycemia. Such problems do not appear to occur as frequently in Type 2 diabetes. This is likely because of pathophysiologic differences between Type 1 and Type 2 diabetes, particularly in:
- Endogenous insulin secretory ability
- Insulin resistance
- Counter-regulatory mechanisms.
There are a number of important aspects of intensive glucose control with insulin in obese patients with Type 2 diabetes:
- First, the average daily dose of insulin needed to aggressively control such patients may approximate one unit per kilogram of body weight.
- Second, the total daily insulin requirement can successfully be split equally between the prebreakfast and predinner injections.
- Third, obese patients will require approximately 70% of their total insulin requirement as NPH with the remainder as a mealtime insulin, such as Humalog, Novolog, Apidra, or regular insulin.
- Fourth, the split-mixed regimen in obese patients with Type 2 diabetes is usually devoid of the common problems seen with this regimen in Type 1 diabetes, particularly early morning hypoglycemia and fasting (preprandial) hyperglycemia.
- Fifth, mild and severe hypoglycemic events are much less frequent in patients with Type 2 diabetes mellitus compared with patients with Type 1 diabetes undergoing intensive insulin therapy.
- Sixth, the use of fast-acting insulin analogues instead of the older regular insulins may be helpful in terms of reducing prolonged postprandial hyperglycemia, A1c, and the incidence of delayed hypoglycemia.
- Finally, weight gain with peripheral hyperinsulinemia frequently occurs in Type 2 diabetes when glucose control is intensified with insulin therapy.
There are several acceptable methods to initiate insulin therapy in Type 2 diabetes. A simple alternative method to initiating a split-mixed regimen in obese patients uses Novolog Mix 70/30 or Humalog Mix 75/25 with an initial total daily insulin dose (0.4 to 0.8 units/kg) equally split between the prebreakfast and predinner injections. Adjustments are made based on SMBG results, which may dictate the need to change the ratio of intermediate- to fast-acting insulin either upward or downward or transitioning to a multiple-daily-injection (MDI) regimen. For morbidly obese patients, the insulin requirements rise dramatically as ideal body weight increases above 150%. In contrast, caution should be used when starting thin patients with Type 2 diabetes on insulin, especially premixed insulins with fixed doses of fast-acting insulin (initial total daily dose 0.2 to 0.5units/kg). This group tends to be more sensitive to the glucose-lowering effects and thus more prone to severe hypoglycemia.
More intensive insulin regimens with MDIs will be needed for those patients who do not achieve glycemic goals with combination therapy and the split-mixed, two-injections-per-day regimen. The basal bolus insulin strategy, which can be utilized in patients with either Type 1 or Type 2 diabetes, incorporates the concept of providing continuous basal insulin secretion throughout the day and night, with brief increases in insulin levels at the time of meal ingestion via bolus doses. A strategy that provides for some flexibility is the mealtime administration of the rapid-acting insulin analogues administered immediately prior to meals, and as intermediate- and long-acting insulins (e.g., NPH, glargine, detemir) as the basal insulin. NPH, which exhibits peak action 5 to 7 hours after administration, has also been utilized in combination with rapid-acting insulin analogues. It is commonly given twice daily, although the disadvantages of NPH used in this manner are similar to those previously associated with Ultralente. Because of its time to peak action, NPH should be given every 6 hours (4 times per day) to be effective as a basal insulin in many patients.
Improved mealtime glucose control with the rapid-acting analogues has exposed the gaps in basal insulin coverage provided by therapy with the traditional intermediate-acting and long-acting insulin preparations. A once-daily basal insulin analogue (e.g., insulin glargine or detemir) with a relatively smooth pharmacokinetic profile would result in a more physiologic pattern of basal insulin replacement. Both insulin glargine and detemir in combination with rapid-acting insulin has demonstrated effective glycemic control and a lower incidence of nocturnal hypoglycemia than with other insulin preparations currently used for basal insulin supplementation.
In summary, there is not a perfect insulin regimen for all insulin-requiring patients with Type 2 diabetes. There is a natural progression of insulin regimens as there is a natural history of Type 2 diabetes. Combination therapy with a bedtime intermediate-acting or long-acting insulin is an easy first t step when initiating insulin therapy. If glycemic goals are not met with the split-mixed regimen, considering premixed insulin can be an easy transition and can be especially effective in obese patients. A natural transition from the more simple regimens is the basal bolus MDI regimen, with a fast-acting analogue before meals and a long-acting basal insulin (e.g., glargine) given once a day.
Robert R. Henry, MD, Professor of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego
Next Week: Part 6: Insulin-Pump Therapy and New Types of Insulin Preparations