Carrie A. Phillips, M.D.

Type 2 diabetes has traditionally been treated in a stepwise manner, starting with lifestyle modifications (nutrition therapy and exercise), proceeding to the use of one oral antidiabetic agent, followed by a combination of 2 or more oral agents before insulin is considered. Treatment is often conservative and allows an oral agent to fail before another one is added and generally delays institution of insulin therapy. Many studies support a more aggressive approach to the treatment of type 2 diabetes to achieve and maintain glycemic levels at target values in an effort to reduce diabetes-related microvascular and macrovascular complications.

Once the decision to begin insulin therapy is made, a strategy to achieve treatment goals while minimizing treatment-related side effects must be determined. In addition, much thought should be given of how insulin therapy may impact lifestyle and how to make the therapy acceptable. In contrast to individuals with type 1 diabetes who must accept full insulin replacement from the start, most people with type 2 diabetes on oral medications resist the idea of injecting insulin until convinced of the actual need for and the benefits of this therapy. Thus, there are major advantages in devising simple approaches that are both acceptable and effective.

Numerous studies have evaluated the addition of insulin therapy to ongoing treatment with oral agents, yet there remains a debate whether one should start with one injection daily for basal insulin needs or use multiple injections to cover both basal and meal-related insulin requirements.

Basal Insulin Supplementation

Clinical studies have shown that a single evening or bedtime injection of basal insulin (Table 1), with the continued use of one or more oral agents, lowers fasting hyperglycemia with a beneficial carryover effect on glycemic levels later in the day. In the Treat-To-Target Trial, patients continued their oral agents and started on one bedtime injection of NPH insulin or insulin glargine. Based on the results, the majority of patients attained excellent glycemic control. However, over 40% of patients did not achieve therapy goals.

Table 1.  Intermediate- and Long-Acting Insulins for Basal Supplementation

Name	Onset	Peak	Duration
NPH	2-4 hrs	4-6 hrs	12-16 hrs
Lente	2-4	4-12	12-18
Ultralente	6-10	unpredictable	18-20
Glargine (Lantus)	2	flat	about 24

Some limitations of basal insulin supplementation include the following: (1) NPH insulin has a peak at 4-6 hours and duration of 12-16 hours, which may lead to nocturnal hypoglycemia or fasting hyperglycemia, and its absorption is subject to significant variations. (2) Lente and ultralente insulins last longer but have similar unpredictable variability. (3) Insulin glargine significantly lowers the risk of hypoglycemia (especially nocturnal hypoglycemia) because of its even release over 24 hours, but it may leave post-prandial (after meal) glucose levels higher than desired.

The results of the Treat-To-Target Trial underscores the fact that many patients will not achieve glycemic goals with the addition of a once-daily basal insulin injection. The most common reason is insufficient control of post-prandial hyperglycemia. Other reasons include nocturnal hypoglycemia, and daytime hypoglycemia when meals are skipped or delayed.

Basal-Bolus Insulin

A basal-bolus insulin regimen mimics physiologic insulin secretion. Injection of a short- or rapid-acting insulin (Table 2) before meals and an intermediate- or long-acting insulin for basal supplementation should be the standard of care in all individuals with type 1 diabetes and should strongly be considered for patients with type 2 diabetes not achieving recommended glycemic goals on their current therapy. A basal-bolus strategy is associated with improved glycemic control and allows the patient greater flexibility in terms of meal timing and even greater flexibility in meal content if the patient is willing and able to learn how to estimate the carbohydrate content of a meal and match it to a pre-determined insulin-to-carbohydrate ratio. Short- or rapid-acting boluses can be started once a day to cover the meal with the highest post-prandial blood glucose values, and advanced to cover the other meals as the need arises.

Table 2.  Short- and Rapid-Acting Insulins for Pre-meal Boluses

Name	Onset	Peak	Duration
Regular	30-60 min	2-4 hrs	6-8 hrs
Lispro (Humalog)	5-15	1	4-5
Aspart (Novolog)	5-15	1	4-5

With regard to the concomitant use of oral agents, the decision to continue or stop specific medications need to be individualized.

For those who prefer to avoid multiple injections of insulin daily but require basal-bolus insulin therapy, combinations of short- or rapid-acting insulin with intermediate-acting insulin can be considered. This strategy can be achieved by using either premixed insulins or split-mix insulin regimens twice daily before breakfast and dinner. Several premixed insulin combinations are available (Table 3). The premixed insulins are simple to use but do not allow the dose of each component to be adjusted separately. A split-mix regimen allows the patient to vary combinations of short- or rapid-acting insulin and intermediate-acting insulin by mixing the two insulins in the same syringe. However, limiting the number of insulin injections to twice daily may leave the patient more susceptible to hypoglycemia and may not achieve recommended glycemic goals.

Table 3.  Pre-Mixed Insulins

Name	Fast-acting Insulin Component	Slow-acting Insulin Component
Novolin or   Humulin 70/30	30% Regular	70% Protaminated   Regular (NPH)
Humalog 75/25	25% Lispro	75% Protaminated Lispro
Novolog Mix 70/30	30% Aspart	70% Protaminated Aspart

The goal of treatment of patients with diabetes should be to achieve and maintain near-normal glycemic control without increasing the risk of hypoglycemia. Nutrition therapy and exercise form the cornerstone of therapy for type 2 diabetes mellitus, but medication is eventually needed in a vast majority of patients in order to maintain excellent glycemic control. When insulin is needed, the addition of a basal insulin or a basal-bolus insulin regimen to oral therapy has proven to be a practical and effective strategy to achieve glycemic goals. With a more aggressive treatment approach and earlier institution of oral and/or insulin therapy when needed, patients will be more likely to achieve glycemic goals, which will reduce the risk of the development and progression of diabetes-related complications.


You can find Dr. Carrie Phillips at AZ Endocrinology, Diabetes & Osteoporosis Ctr., 5130 W. Thunderbird Rd., Suite 1, Glendale, AZ 85306