Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes

Philip Levy, MD, FACE


April 16, 2007

Progression of Therapy in Patients With Type 2 Diabetes

Type 2 diabetes management has traditionally followed a stepwise approach, beginning first with diet and exercise, then adding 1 or more OADs when dietary modifications and exercise are inadequate.[18] Algorithms for the management of diabetes have been developed by AACE/American College of Endocrinology (ACE)[18] and ADA/European Association for the Study of Diabetes (EASD).[11] Both stress tight glycemic control, rapid addition of medications or transition to new regimens when goals are not met, and early insulin therapy, particularly when A1C levels are greater than 8.5% or severe hyperglycemia (FPG >250 mg/dL) is present.[11,18]

Because the pathophysiology of type 2 diabetes involves both insulin resistance and progressive failure of beta-cells to secrete insulin, various OADs have been developed to increase insulin secretion (insulin secretagogues) and insulin sensitivity (insulin sensitizers) ( Table 2 ).[19] The alpha-glucosidase inhibitors (AGIs) are another class of agents that act by delaying intestinal carbohydrate absorption, but have limited A1C-lowering capacity (0.5% to 0.8%).[11]

The recent consensus recommendation from the ADA/EASD is to begin metformin as the initial step in type 2 diabetes management, along with diet and exercise.[11] Before this more aggressive approach, pharmacotherapy was often initiated with an insulin sensitizer (metformin or a thiazolidinedione) or an oral secretagogue (a meglitinide or sulfonylurea).[20] Monotherapy usually results in initial treatment success followed by a slow, but steady, rise in A1C.[10,21,22,23] A recent study of patients receiving oral monotherapies including metformin, rosiglitazone, or glyburide reported that 60%, 64%, and 76%, respectively, had A1Cs of 7% or higher after the fourth year of follow-up.[24] Combination oral therapy with a secretagogue and sensitizer is typically the next step,[18] although some patients, such as those whose blood glucose greatly exceeds treatment goals, may actually begin treatment using combination OAD therapy.[25] Several newer therapies, both injectable and oral, are now available and may be added ( Table 2 ; discussed subsequently).

Although initiation of insulin therapy was typically uncommon in type 2 diabetes management until after oral agents failed,[26,27,28,29] the paradigm for diabetes management has been shifting. Because beta-cell failure is progressive, most patients with type 2 diabetes will ultimately require insulin therapy to achieve glycemic goals, and thus insulin should no longer be considered a last resort because of failure or fault of the patient. Rather, there is an emerging awareness that using insulin earlier in the course of disease is physiologically sound and an integral part of adequate disease management.[29,30,31] Delays in starting patients with type 2 diabetes on insulin may be due to patient resistance or physician uncertainty about how to make this transition.[32] Reluctance to initiate more aggressive therapy, particularly insulin, or concern about hypoglycemia, may explain why ideal glycemic control still has not been achieved.[33]


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