Addition of Basal Insulin to Oral Antidiabetic Agents: A Goal-Directed Approach to Type 2 Diabetes Therapy

Louis Kuritzky, MD


November 15, 2006

Rationale for Combination Therapy

As the disease progresses, many patients with type 2 diabetes will eventually be unable to adequately achieve or maintain glycemic control, whether monotherapy or combination oral therapies are employed. The reason for diminishing antihyperglycemic effects with oral agents over time is multifactorial and includes progressive loss of beta-cell function,[24,25] comorbidities, lifestyle factors, and possibly glucotoxicity. In most cases, patients on oral antidiabetic therapy will require not only an increase in dose but also the addition of a second or third oral agent.[26,27] As the number and dosage of oral agents increases, the side-effect profile, regimen complexity, and expense rise commensurately.

One fundamental obstacle to achieving glycemic control with oral agents is their limited capacity to reduce overall A1C levels in patients presenting with relatively high levels (> 10.0%). The expected reduction in A1C with maximum doses of oral antidiabetic agents in combination therapy is approximately 3.0% ( Table 1 ). Accordingly, it is unlikely that patients presenting with A1C > 10.0% will achieve treatment goals on oral agents alone. These agents should, however, be added sequentially without delay. Physicians should also not delay in advancing therapy if it becomes apparent that combination therapy is either not reducing hyperglycemia quickly enough or that the efficacy of individual agents has reached its maximum benefit and can no longer contribute to improving glycemic parameters. An algorithm for treating patients with type 2 diabetes with insulin and oral therapy is shown in the Figure.[28]

Figure 1.

Algorithm for management of type 2 diabetes.

In contrast to the diminishing benefits obtained from therapy with multiple oral antidiabetic agents, combining insulin therapy with oral agents may allow patients to reach and maintain glycemic goals.[29,30] The combination of oral agents with insulin may sometimes mitigate hypoglycemia and weight gain observed with insulin monotherapy.[31,32] Another possible benefit of combining oral agents with insulin is improvement of lipid profiles.[32,33] A recent position statement from the Implementation Conference for the American College of Endocrinology Outpatient Diabetes Mellitus Consensus Conference[34] indicated that insulin in combination with oral agents or basal-bolus regimens (ie, basal insulin in combination with bolus insulin, such as aspart, glulisine, or lispro) should be considered at an early stage in type 2 diabetes if glycemic goals are not readily attained and maintained with oral agents alone. Premixed insulin preparations were recommended to be used only in special situations.

Patients should be made aware at the inception of type 2 diabetes therapy that, because it is generally a progressive disorder, at some time in their treatment programs it is likely that insulin will be employed due to its advantage of attaining control when other methods can no longer maintain control. Rather than posture insulin treatment as being instituted because "they" (the patients) have failed or "the drugs" have failed, incorporating a stance that fosters progressive treatment selection based on the likelihood of clinical success (ie, achievement of goal A1C) prepares patients for the possibility that insulin may be a "right" choice at any point in the treatment pathway. An analysis of data from published clinical studies supports the use of bedtime insulin combined with ≥ 1 oral antidiabetic agents for patients poorly controlled on other regimens.[4,29]


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