Case Study:
Mrs. Gomez & Gestational Diabetes

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What general intervention strategies are indicated?

Treat the ABCs

• A1C
• Blood Pressure
• Cholesterol

Reduce weight
Refer to dietitian for nutrition counseling
Recommend increased physical activity

What pharmacologic interventions would you recommend to reduce the plasma glucose and the percent A1C?

Intervention 1: Monotherapy

Because she is overweight, has elevated morning glucose levels, and a normal Chem 18 (normal liver function tests and creatinine), treatment could begin with metformin (Glucophage). Additional monotherapies could include sulfonylureas (SFUs), meglitinides (repaglinide or nateglinide, Prandin or Starlix respectively), or a thiazolidinedione (TZD), (rosiglitazone or pioglitazone, Avandia or Actos respectively).

As a general rule, for every class of anti-hyperglycemic drug added to the patient's therapy (including diet and exercise as a class of intervention), the A1C should drop by approximately 1-1½%.⁹ This patient has an A1C that is 2% above ADA's recommended guidelines (<7% A1C) and 2½% above American Association of Clinical Endocrinologists' guidelines¹⁰ (<6.5% A1C). Therefore at least one and likely two drug classes would help her reach target levels.

Intervention 2: Combination therapy

Combination therapy could be started first line or upon failing to get to target with monotherapy.

SFU + MET or TZD + MET: When starting combination therapy, consider the potential side effects, especially hypoglycemia. Since SFUs are insulin secretagogues, they can cause hypoglycemia, especially when used in combination therapy. For example, when using SFU and MET in combination, the risk of hypoglycemia increases because of their superimposed modes of action. An SFU increases the release of insulin from the pancreas and MET mainly inhibits glucose production, which occurs in the liver (nocturnal gluconeogenesis). A patient may have a higher risk of hypoglycemia as a result of the increased release of insulin from the secreatagogue: while MET inhibits glucose production. The patient is inhibited from their normal compensatory response to hypoglycemia, i.e., gluconeogenesis. These two mechanisms leave the patient at a greater risk of nocturnal or morning hypoglycemia. In contrast, combination MET and TZD therapy has very low hypoglycemic risk.

One new consideration in combination therapy is the addition of an incretin mimetic. In April 2005, the FDA approved the first incretin in its class. Incretins are "gut-derived factors that increase glucose-stimulated insulin secretion."¹¹ Exenatide (Byetta), an incretin mimetic, has been approved for use in combination with MET and/or SFU. Exenatide increases the release of insulin from the pancreas, decreases glucagon released by the pancreatic α-cells, stimulates the satiety centers in the hypothalamus, and slows gastric emptying. It has also been shown to induce weight loss, reduce A1C and improve β-cell function.^{12, 13}

Intervention 3: Combination therapy with Insulin

Add third oral combination to therapy
Add insulin
Switch to insulin

In addressing the progressive nature of β-cell decline resulting in the deterioration of glycemic control, one should consider not only the fasting glucose levels but also the frequently elevated postprandial glucose levels.

TZD + Secretagogue: Using a TZD in combination with a meglitinide may help reduce postprandial glucose level by combining the effect of an insulin sensitizer (TZD) with that of a rapid insulin secretagogue (meglitinide). If morning glucoses are elevated, you may add MET. If postprandial glucoses are still elevated while using TZD/meglitinide combination therapy, adding MET will not effectively address the postprandial glucose elevation (since MET primarily reduces nocturnal gluconeogenesis). In this case, adding an insulin analog may reduce postprandial glucose. This might be achieved by discontinuing the secretagogue and adding insulin (bolus insulin or basal/bolus combination).

TZD + MET: If you need to reduce postprandial glucoses, you could add an insulin secretagogue, while using a TZD in combination with MET, such as meglitinide or an SFU. If morning glucose levels are still elevated, you may consider adding a basal insulin. Postprandial glucoses will probably also be elevated when the fasting glucoses are poorly controlled. At that point, adding a basal/bolus insulin regimen may be more effective.

When adding an insulin, whether basal with bolus or mixed insulin {i.e., 70/30 with regular or analog (insulin aspart) or 75/25 with analog (insulin lispro)}, one should keep in mind to check not only the morning glucose but the postprandial glucose levels as well. Current postprandial guidelines are peak postprandial glucose levels of <180 mg/dL¹⁴; or 2hPP glucose levels <140 mg/dL.¹⁵ Staggering the patient's self blood glucose monitoring will help find the elevated glucoses, which are usually postprandial.

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