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Weighing the Options in the Battle for Glycemic Control


What should be added to the regimen of a patient with type 2 diabetes mellitus when initial oral therapy no longer adequately controls glucose levels?

What should be added to the regimen of a patient with type 2 diabetes mellitus when initial oral therapy no longer adequately controls glucose levels?

The increasing disease burden of type 2 diabetes mellitus is well known, especially to primary care physicians. It has truly become a contemporary epidemic. It is also apparent that poor glycemic control is responsible for microvascular and, to some degree, macrovascular complications, which can be fatal.

Now therein lies the rub. Although hemoglobin A1c (HbA1c) concentrations of less than 7% are the target, they are difficult to reach and maintain. Even if control is achieved early in the course of the disease, oral hypoglycemic agents (such as sulfonylureas and metformin) fail over time (usually a few years) in about 50% of patients and additional therapy is required.1 What should be added to the regimen of these patients?


A recent paper describes a typical clinical scenario.2 A 55-year-old woman with type 2 diabetes, obesity, and hypertension has had effective glycemic control with metformin, 1000 mg bid, and glipizide, 10 mg bid. After 2 years, her HbA1c level increases to 8.1%, although she remains free of microvascular complications. What should her primary care physician do?

In this paper, 3 experts recommend and defend 3 options: adding pioglitazone, NPH insulin at bedtime, or twice-daily exenatide. The advantages, justified by evidence-based medicine, of adding pioglitazone are:

  • A delay in initiating insulin.

  • Sensitization to insulin if it is started later.

  • A 2% reduction in HbA1c levels (similar in magnitude to that achieved with insulin).

  • Compared with insulin, less hypoglycemia and a higher high-density lipoprotein cholesterol level.

  • Once-daily dosing.

The benefits of NPH insulin are lower cost; greater efficacy than oral medications; less weight gain; and no increase in the risk of edema, heart failure, and fractures,3 which are all associated with thiazolidinediones such as pioglitazone. Adding exenatide twice daily can lead to weight loss and better control of postprandial glucose because of delayed gastric emptying. Clinicians were able to log in at www.nejm.org to express their specific treatment preference.


A perfect companion piece to this article is a paper that compared the use of once-daily glargine insulin with 3 doses of postprandial insulin in patients in whom oral medications had failed.1 The 2 strategies were equally effective; however, once-daily glargine resulted in fewer episodes of hypoglycemia, fewer injections (obviously), decreased requirements for glucose monitoring and, as a result, greater patient satisfaction.

There are numerous options for diabetes treatment when oral agents predictably fail over time. The primary care physician’s clinical gestalt and personal knowledge of individual patients allow for some latitude in choice.




Bretzel RG, Nuber U, Landgraf W, et al. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial.




. Goldberg RB, Holman R, Drucker DJ. Clinical decisions: management of type 2 diabetes.

N Engl J Med.



Meier C, Kraenzlin ME, Bodmer M, et al. Use of thiazolidinediones and fracture risk.

Arch Intern Med.


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