VOL. 17 NO. 3 1999

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A Practical Approach to Combination Therapy: Daytime Oral Agent(s) and Bedtime NPH Insulin

Steven V. Edelman, MD

The benefits of normalizing glycosylated hemoglobin in patients with type 1 or type 2 diabetes mellitus have been clearly demonstrated by the results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS).

It is now strongly recommended that the glycemic objective for patients with type 2 diabetes should be similar to that for type 1 diabetes: to normalize glycemia and glycosylated hemoglobin concentrations. This article looks at the clinical benefits of combination therapy of bedtime NPH insulin and daytime oral agent(s). There is no widely accepted, standard form of insulin therapy for patients with type 2 diabetes. However, combination therapy can be effective, easy to apply, and safe.

One area of major concern when insulin therapy is used to achieve tight glucose control in type 2 diabetes is the well-recognized association of hyperinsulinemia with weight gain and accelerated atherosclerosis. Although the links between these complications and hyperinsulinemia do not necessarily indicate a cause-and-effect relationship, it is the general practice that therapeutic interventions other than exogenous insulin should be thoroughly attempted first. In addition, when diet, exercise, and oral antidiabetic agents fail to control glycemia, then the lowest possible dose of insulin should be used to minimize peripheral hyperinsulinemia and the possible consequences of this form of therapy. Combination therapy may offer the most effective way of achieving glycemic control while minimizing hyperinsulinemia and weight gain seen with multiple injection regimens in type 2 diabetes.

An important aspect of the pathophysiology of hyperglycemia in type 2 diabetes deserves comment when insulin therapy is used to achieve normalization of glycemia and the glycosylated hemoglobin. The classic glycemic profile of type 2 diabetes consists of elevated basal or fasting glucose concentrations on which postprandial glycemic excursions are superimposed. Clearly, the basal rate of hepatic glucose production is the primary determinant of the fasting plasma glucose concentration in type 2 diabetes. Postprandial hyperglycemia is determined, in large part, by peripheral glucose utilization and the severity of insulin resistance. In type 2 diabetes, however, hepatic glucose output is more sensitive to suppression by insulin than is stimulation of glucose uptake, which usually requires the presence of high pharmacological concentrations of circulating insulin.

This is particularly important when striving to achieve normoglycemia in the obese form of type 2 diabetes, in which exogenous insulin acts primarily to suppress excessive hepatic glucose output rather than to stimulate peripheral glucose uptake. Because the degree of peripheral insulinemia has been directly linked to the development of weight gain when trying to achieve tight metabolic control, one should consider using only the amount of exogenous insulin that is necessary to suppress hepatic glucose output and achieve normal fasting glucose concentrations. This can be achieved by adding bedtime NPH insulin to daytime oral agents.

Application of Insulin Therapy
The goals of therapy should be individually tailored. Candidates for intensive management should be motivated, compliant, and educable, without other medical conditions and physical limitations that preclude accurate and reliable self-monitoring of blood glucose and insulin administration. In addition, caution is advised in patients who are aged or have hypoglycemic unawareness. Other limitations to achieving normoglycemia may include high titers of insulin antibodies, especially in patients with a history of intermittent use of insulin of animal origin.

The site of insulin injection may also change the pharmacokinetics, and absorption can be highly variable, especially if lipohypertrophy is present. The periumbilical area has been shown to be one of the most desirable areas to inject insulin because of the rapid and consistent absorption kinetics observed at this location.

Before starting insulin therapy, patients should be well educated in the techniques of blood glucose self-monitoring, proper insulin administration, and self-adjustment of the insulin dose, if appropriate. Patients should also be knowledgeable about dietary and exercise strategies. Patients and their family members also need to be informed about hypoglycemia prevention, recognition, and treatment. Initial and ongoing education by a diabetes management team is crucial for long-term success and safety.

Combination Therapy
Combination therapy usually refers to the use of oral antidiabetic agents together with a single injection of intermediate-acting insulin at bedtime. The rationale for using an evening insulin strategy is based on the patho-physiology of fasting hyperglycemia in type 2 diabetes. Combination therapy is based on the assumption that if evening insulin lowers the fasting glucose concentration to normal, then daytime sulfonylureas and any other oral agent now on the market will be more effective in controlling glycemia throughout the day.

The fasting blood glucose concentration is highly correlated with the degree of hepatic glucose production during the early morning hours. Hepatic glucose output is directly suppressed by insulin. Bedtime intermediate-acting insulin also has its peak action coinciding with the onset of the dawn phenomenon (early morning resistance to insulin due to diurnal variations in growth hormone), which usually occurs between 3:00 and 7:00 a.m. Bedtime insulin also increases the morning serum insulin concentration and may assist in reducing the post-breakfast glucose in addition to the fasting value.

Patient selection is very important when considering combination therapy. The question of whether a patient is still responding in a satisfactory manner to oral antidiabetic agents, such as sulfonylureas, repaglinide (Prandin), metformin (Glucophage), or troglitazone (Rezulin), is of primary importance. Patients have a higher likelihood of success using daytime oral agent(s) and bedtime insulin if they are obese, have had overt diabetes for <10–5 years, are diagnosed with type 2 diabetes after the age of 35, have fasting blood glucose values consistently <250–300 mg/dl, and have evidence of endogenous insulin secretory ability.

Patients with type 2 diabetes diagnosed before the age of 35 more often have atypical forms of diabetes. Patients with diabetes for >10–15 years tend to have a greater chance of pancreatic exhaustion and thus may be less responsive to oral hypoglycemic agents during the day. Thin patients are more likely to be insulinopenic and often respond inadequately to oral agents, which leads to combination therapy failure. In addition, when the fasting glucose concentration becomes markedly elevated, this is often associated with a concomitant decrease in endogenous insulin secretory ability, which renders oral agents ineffective. Studies demonstrating the most favorable outcome from combination therapy have utilized patients who still had some response to oral agents or had evidence of significant endogenous secretory ability.

The actual number of patients who might fit into this category and possibly respond to combination therapy is unknown, but it is estimated to be 20–40% of all patients failing with maximum doses of sulfonylureas or other oral agents as the sole therapy.

Table 1. Advantages of Combination Therapy
  • Easy to teach (no insulin mixing)
  • Only one injection per day in the evening
  • Lower doses of insulin are needed, usually
    resulting in less weight gain
  • Patients who later need a multiple injection
    regimen have had a chance to get over any needle

There are also a number of practical reasons why combination therapy may be beneficial (Table 1). Patients do not need to learn how to mix different types of insulin; hospitalization is not required; and patient compliance and acceptance are better with a single injection than with multiple injections of insulin. Combination therapy also requires a lower total dose of exogenous insulin than a full two- or three-injection-per-day regimen. This usually contributes to less weight gain and peripheral hyperinsulinemia. This is especially true with the use of daytime metformin, acarbose, or troglitazone, since these agents do not stimulate pancreatic insulin secretion.

Calculation of the initial bedtime dose of intermediate-acting insulin can be based on clinical judgment or various formulas based on the fasting blood glucose concentration or body weight. For example, one can divide the average fasting blood glucose (mg/dl) by 18 or divide the body weight (kilograms) by 10 to calculate the initial dose of NPH or lente insulin to be started at bedtime. One can also safely start 7–10 U of intermediate-acting insulin for thin patients and 12–15 U for obese patients at bedtime as an initial estimated dose. In either case, the dose is increased in 2- to 5-U increments every 3–4 days until the morning fasting blood glucose concentration is consistently in the range of 70–140 mg/dl.

The best time to give the evening injection of intermediate-acting insulin is between 10:00 p.m. and midnight. Many reliable patients can make their own adjustments using self-monitoring of blood glucose. The accompanying Patient Information page is an instruction sheet for patients' use in making bedtime insulin adjustments. Once the fasting blood glucose concentrations are consistently in a desirable range, the pre-lunch, pre-dinner, and bedtime blood glucose values must be monitored to determine if the oral hypoglycemic agents are maintaining daylong glycemia.

Based on glucose self-monitoring results, combination therapy can be altered to reduce hyperglycemia at identified times during the day. For example, a common situation seen with daytime oral agent(s) and bedtime intermediate-acting insulin therapy is an improvement in the fasting, pre-lunch, and pre-dinner blood glucose values, although the post-dinner blood glucose concentration remains excessively high (>200 mg/dl). In this clinical situation, an injection of premixed regular and intermediate-acting insulin (i.e., 70/30 insulin) before dinner instead of a bedtime dose of intermediate-acting insulin may be more efficacious. This regimen will often improve the post-dinner blood glucose values because the premixed insulin contains regular insulin yet still allows overnight glucose control secondary to the intermediate-acting component. With this regimen, however, one must be more cautious about early morning hypoglycemia because the intermediate-acting insulin given before dinner will exert its peak effect earlier. In my experience, this has not been a major clinical problem in patients with type 2 diabetes compared to those with type 1 diabetes mellitus.

It is recommended that after the addition of evening insulin, patients continue to take their maximal dose of oral antidiabetic agent(s). If the daytime blood glucose concentrations start to become excessively low, the dose of oral medication must be reduced. If the patient is on multiple antidiabetic agents, then the sulfonylurea or repaglinide should be reduced first. This situation is not uncommon because glucose toxicity may be reduced due to improved glucose control, leading to enhanced sensitivity to both oral agents and insulin. If the pre-lunch and pre-dinner blood glucose concentrations remain excessively high on combination therapy, the oral antidiabetic agent is likely not contributing significantly to glycemic control throughout the day. In this situation, a more conventional two-injection-a-day regimen should be employed, discontinuing the oral antidiabetic agent(s).

In summary, combination therapy can be a simple and effective means of normalizing glycemia and glycosylated hemoglobin concentrations in selected patients with type 2 diabetes mellitus who fail with oral antidiabetic agents. The most common type of patient in whom combination therapy can succeed is the one who fails oral agent therapy but has some evidence of responsiveness. Bedtime intermediate-acting insulin is given and progressively increased to normalize the fasting blood glucose concentration. When the fasting blood glucose is brought under control, the success of combination therapy depends on the ability of the daytime oral antidiabetic agents to maintain euglycemia. If this cannot be achieved, then the oral hypoglycemic agents should be stopped and conventional insulin regimens should be employed.

Steven V. Edelman, MD, is an associate professor of medicine in the Division of Endocrinology, Metabolism, and Diabetes and co-director of the Endocrine Fellowship Training Program at the University of California at San Diego and the San Diego Veterans Affairs Medical Center. He is also founder of Taking Control of Your Diabetes, a nonprofit organization promoting patient education and motivation. He is an associate editor of Clinical Diabetes.

Copyright 1999 American Diabetes Association
Updated 7/99
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