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Diagnosis and Management of Type 2 Diabetes, 10th Edition, Ch 9-Pt 4

Combination Therapy, Chapter 9 – Part 4


Steve V. Edelman, MD

Robert R. Henry, MD

Combination therapy usually refers to the use of oral antidiabetic agents (daytime) together with a single injection of intermediate-acting or long-acting insulin at bedtime. The rationale for using an evening-insulin strategy is based on the pathophysiology of fasting hyperglycemia in type 2 diabetes. The underlying tenet for combination therapy assumes that….

if evening insulin lowers the fasting glucose level to normal levels, the daytime oral agent will be more effective at controlling postprandial hyperglycemia and maintaining euglycemia throughout the day. Metabolic profiles in type 2 diabetes have clearly demonstrated that the FBG is a major determinant or predictor of glycemic control throughout the day. The FBG level is highly correlated with the degree of hepatic glucose production during the early morning hours, which is suppressed by bedtime insulin. In addition, bedtime intermediate-acting insulin’s peak action coincides with the onset of the dawn phenomenon (early morning resistance to insulin caused by diurnal variations in growth hormone and possibly norepinephrine levels), which usually occurs between 3 and 7 AM.

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 agent(s), such as sulfonylureas (SFUs), is of primary importance. Patients also have a higher likelihood of success using daytime oral agents and bedtime insulin if they:

• Are obese

• Have had overt diabetes for

• Are diagnosed with type 2 diabetes after the age of 35

• Do not have FBG values consistently >250 to 300 mg/dL

• Have evidence of endogenous insulin secretory ability.

Although standard measurement conditions and levels for C-peptide have not been established for this clinical situation, a fasting (0.2 nmol/L or 0.6 ng/mL) or glucagon stimulated (>0.40 nmol/L or 1.2 ng/mL) C-peptide value indicates some degree of endogenous insulin secretory ability. Patients with type 2 diabetes diagnosed under the age of 35 more often have atypical forms of diabetes. Subjects with diabetes longer than 10 to 15 years in duration tend to have a greater chance of cell exhaustion and thus be less responsive to the oral antidiabetic agents.

Thin patients are more likely to be hypoinsulinemic and often respond inadequately to oral SFUs, which leads to combination-therapy failure. In addition, when the fasting glucose level becomes markedly elevated, this is often associated with a concomitant decrease in endogenous insulin secretory ability, which renders oral agents less effective. The actual number of patients who might fit into this category and possibly respond to combination therapy is unknown but is estimated to be between 20% and 30% of all patients in whom maximum doses of oral agent therapy fail.

There are also a number of practical reasons why combination therapy may be beneficial (Table 9.2):

• The patient does not need to learn how to mix different types of insulin

• Hospitalization is not required

• Patient compliance and acceptance are better with single rather than multiple injections of insulin

• The patient does not need to take injections during work or other activities

• It enables the patient to be initiated to insulin in a simple straightforward manner.

Combination therapy also requires a lower total dose of exogenous insulin than a full regimen of two or three injections per day. This usually contributes to less weight gain and peripheral hyperinsulinemia.

Calculation of the initial bedtime intermediate acting insulin dose can be based on clinical judgment or on various formulas using FBG level or body weight. For example, one can divide the average FBG (mg/dL) by 18 or divide the body weight in kilograms by 10 to calculate the initial dose of NPH, Lente, or glargine to be started at bedtime. One can also safely start 5 to 10 units of intermediate-acting or long-acting insulin (NPH, Lente, or glargine) for thin patients and 10 to 15 units for obese patients at bedtime as an initial estimated dose. In either case, the dose is increased in 2- to 5-unit increments every 3 to 4 days until the morning FBG level is consistently in the range of 80 to 140 mg/dL (Table 9.3).

The ideal time to give the evening injection of intermediate-acting or long-acting insulin is between 10PM and midnight. Many reliable patients can make their own adjustments using SMBG. Table 9.4 demonstrates a patient self-instruction sheet for bedtime insulin adjustments. Once the FBG levels are consistently in a desirable range, the prelunch, predinner, and bedtime blood glucose must be monitored to determine if the oral hypoglycemic agents are maintaining daytime euglycemia. If glucose toxicity is present, the patient should wait for a few weeks of normal or near-normal prebreakfast blood glucose values before monitoring for daytime control.


Based on the results of SMBG, combination therapy can be altered to reduce hyperglycemia at identified times during the day. For example, a common situation seen with daytime SFUs and bedtime intermediate-acting or long-acting insulin is an improvement in the fasting, pre-lunch, and pre-dinner blood glucose, although the post-dinner blood glucose level remains excessively high (>200 mg/dL). In this clinical situation, an injection of premixed fast-acting analogue and intermediate-acting insulin (i.e., Humalog Mix 75/25 or Novolog Mix 70/30) pre-dinner instead of the bedtime dose of intermediate-acting insulin may be more efficacious (Table 9.5). This regimen will often improve the post dinner blood glucose values, because the premixed insulin contains rapidly acting regular insulin yet will still allow overnight

glucose control secondary to the intermediate-acting component. With this regimen, however, one must be more cautious of early morning hypoglycemia because the intermediate insulin given before dinner will exert its peak effect earlier. The latter concern has not been a major clinical problem in patients with type 2 diabetes compared with those with type 1 diabetes.

It is recommended that after addition of evening insulin, patients remain on their maximum dose of oral antidiabetic agent. If the daytime blood glucose levels start to become excessively low, the dose of oral medication must be adjusted downward, especially SFUs. This is not an uncommon scenario because glucose toxicity may be reduced as a result of improved glucose control, leading to enhanced sensitivity to both oral agents and insulin. If the prelunch and predinner blood glucose levels remain excessively high on combination therapy, the oral antidiabetic agent is likely not contributing significantly to glycemic control throughout the day.  In this situation, use of other oral antidiabetic agents can be utilized or a more conventional regimen of two injections per day can be employed while discontinuing the oral antidiabetic agents.

In summary, combination therapy can be a simple and effective tool to normalize glycemia and A1C levels in selected patients with type 2 diabetes mellitus in whom oral antidiabetic agents fail. The most common clinical situation in which combination therapy can be successful is in the patient in whom oral anti diabetic therapy fails but with some evidence of responsiveness to the oral agents. Bedtime intermediate-acting or long-acting insulin is given and progressively increased so as to normalize the FBG level. When the FBG level is brought under control, the success of combination therapy is dependent upon the ability of the daytime oral antidiabetic agents to maintain euglycemia. If this cannot be achieved, other oral antidiabetic agents can be used or conventional insulin regimens employed.

Treat-to-Target Studies

The Treat-to-Target Study demonstrated the ease of administration and effectiveness of combination therapy with oral agents during the day and one injection of insulin glargine or NPH given at night in >400 patients (age ~55 years, ~BMI 32, duration of diabetes ~8 years). In 15 weeks of combination therapy, the average A1C for the two groups decreased from 8.6% to <7.0%, using an aggressive titration schedule for the bedtime insulin with a goal of an FBG Figure 9.4). Both treatment arms were equally effective; however, the insulin glargine group experienced significantly less hypoglycemia during the night (Figure 9.5). In another study that used an aggressive treat-to-target titration protocol, insulin detemir and NPH were equally effective in controlling blood glucose levels when used twice daily as basal insulin, but detemir was associated with fewer hypoglycemic events, especially nocturnal hypoglycemia, in comparison with NPH, and 70% of patients achieved an A1C _7%.

Steve V. Edelman, MD, Professor of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego
Robert R. Henry, MD, Professor of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego
© Copyright 2010. Steven V. Edelman, MD, Robert R. Henry, MD, Professional Communications, Inc. All rights reserved.

Next week, Part 5: Multiple-Injection Regimens and Insulin-Pump Therapy

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