Metformin was chosen as the initial therapy in this adolescent for several reasons, including demonstrated efficacy and tolerability in pediatric studies, approval for use in this population, and because it is generally not associated with weight gain. The patient needs a 1.7% reduction in A1C; therefore, metformin was titrated to the maximum daily dosage of 2,000 mg (expected to, on average, reduce A1C by 1% to 2%). In a recent, randomized, double-blind, placebo-controlled trial of pediatric patients (aged 10 to 16 years) with type 2 diabetes,22 metformin 1,000 mg bid significantly reduced baseline-adjusted mean A1C values compared with placebo (7.5% vs 8.6%, P<0.001) without negatively affecting body weight or lipid levels. The adverse events profile of metformin in children was similar to that observed in adults, primarily involving gastrointestinal events.
CASE 1 Monotherapy inadequate
After 6 months on metformin therapy, the patient returns for follow-up. His A1C measure has improved to 7.7%, but his weight remains unchanged. At this point, a discussion is initiated about using combination therapy to bring his diabetes under control.
This case study illustrates an important point about the treatment of type 2 diabetes: pharmacologic therapy with a single antidiabetic agent often is insufficient to reach target goals for glycemic control.2 Frequently, this reflects the insidious, progressive nature of the disease, which may be present for years before being recognized. As a general rule, combination therapy involves the use of drugs with different mechanisms of action. Clinical trials evaluating combination therapy generally follow this rationale.
Since there are limited pediatric data for the majority of oral agents, the clinical decision regarding which agents to use in combination often is based on the available data in adults. Information regarding efficacy, safety, and tolerability for the different oral antidiabetic drugs used in adults with type 2 diabetes is provided in TABLE 3.
Secretagogues (ie, sulfonylureas and meglitinides) have been reported to typically reduce A1C values by 1% to 2% at maximal doses. Generally, the shorteracting meglitinides have been considered useful for reducing postprandial hyperglycemia and are taken before meals.23 Unlike traditional sulfonylureas, glimepiride also has demonstrated efficacy in controlling postprandial hyperglycemia.24 All patients starting therapy with a secretagogue should be counseled on recognition of hypoglycemic symptoms and appropriate self-treatment. While severe hypoglycemia is not common in type 2 diabetes, it can occur with any agent that increases insulin secretion.
The glitazones lower A1C levels by an estimated 1% to 1.5%. Although they primarily reduce insulin resistance, they also may have beneficial effects on blood lipids, BP, and inflammatory markers associated with CVD, suggesting a theoretical benefit for reducing macrovascular complications.25 Glitazones, however, have been associated with weight gain and fluid retention, which in adults may unmask or exacerbate congestive heart failure.25 Additionally, although pioglitazone and rosiglitazone do not appear to carry the same risk of hepatotoxicity as the first member of the class, troglitazone, there have been a few case reports of liver injury or failure in patients treated with pioglitazone26-28 or rosiglitazone.29-31 In the absence of pediatric and long-term data, caution is warranted with use of these agents in this population.
α-Glucosidase inhibitors are helpful in controlling mealtime glycemic excursions and may have utility in patients who require smaller reductions in A1C. Use of these relatively safe agents is limited due to gastrointestinal side effects (ie, diarrhea and flatulence are common),32 which can prevent titration to optimal doses. Since the primary mechanism of action is inhibition of carbohydrate digestion, patients who are using these agents in combination with therapies that can cause hypoglycemia should be counseled to use simple sugars (ie, glucose tablets) rather than complex carbohydrates to self-treat hypoglycemia.
If oral agents cannot achieve adequate glycemic control, addition of insulin is a rational, well-tolerated, and effective option.3,4,33 Insulin therapy is often underutilized and delayed in patients with type 2 diabetes who would benefit from earlier introduction of such therapy.34 The pediatric experience with insulin is extensive, but mostly in type 1 diabetes. The potential need for and benefits of insulin therapy may be discussed with patients as early as at the time of diagnosis to help alleviate some of the anxiety patients have regarding this therapy.35
TABLE 3
Available oral antidiabetic agents
| DRUG | DAILY DOSE (MG) | DOSES/DAY | PRIMARY MECHANISM(S) | EXPECTED A1C REDUCTION (%) | COMMON ADVERSE EFFECTS |
|---|---|---|---|---|---|
| Sulfonylureas | Augment insulin secretion | 1–2 | Hypoglycemia, weight gain* | ||
| Glimepiride | 1–8 | 1 | |||
| Glipizide | 2.5–40 | 1–2 | |||
| Glipizide controlled release | 2.5–20 | 1 | |||
| Glyburide | 2.5–20 | 1–2 | |||
| Glyburide micronized | 3–12 | 1–2 | |||
| Meglitinides | Augment insulin secretion | 1–2 | Hypoglycemia, weight gain | ||
| Repaglinide | 0.5–16 | 2–4 | |||
| Nateglinide | 360 | 2–4 | |||
| Biguanides | Increase sensitivity to insulin, decrease hepatic glucose production | 1–2 | Gastrointestinal symptoms† | ||
| Metformin† | Adults: 500–2,550 Children (10–16 yr) 500–2,000 | 2–3 | |||
| Thiazolidinediones | Increase sensitivity to insulin | 1–1.5 | Fluid retention, weight gain‡ | ||
| Rosiglitazone | 2–8 | 1–2 | |||
| Pioglitazone | 15–45 | 1 | |||
| α-Glucosidase Inhibitors | Slow digestion of carbohydrates | 0.5–1 | Flatulence, gastro-intestinal discomfort, weight gain | ||
| Acarbose | 75–300 | 3 | |||
| Miglitol | 75–300 | 3 | |||
| *Glimepiride had a neutral effect on weight in clinical studies and was associated with a lower incidence of hypoglycemia than other sulfonylureas.49-51 | |||||
| † Lactic acidosis has been reported with metformin use, but is extremely rare. The risk may be related to an underlying predisposition to lactic acidosis. | |||||
| ‡ There have been some reports of liver toxicity with second-generation thiazolidinediones. | |||||
| Adapted from American Association of Clinical Endocrinologists;21 Nathan DM. Clinical practice. Initial Management of glycemia in type 2 diabetes mellitus.N Engl J Med. 2002;347:1342-1349. | |||||