Treating type 2 diabetes: Targeting the causative factors
Glyburide and chlorpropamide have active metabolites with renal elimination, and they should therefore be used with caution in patients with renal insufficiency. In 1971, the University Group Diabetes Project (UGDP) observed a twofold increase in the rate of cardiovascular death among patients receiving tolbutamide compared with those receiving insulin or placebo.18 This led to a decades long debate on the validity of this conclusion.19 More recently, UKPDS 33 did not demonstrate any increased cardiovascular mortality among patients receiving glyburide or chlorpropamide, and has largely negated this earlier concern.2
Cost. Sulfonylureas are the least expensive oral agents used to treat type 2 diabetes.
TABLE 3
Pharmacological treatments for type 2 diabetes: combination therapies
| Sulfonylureas | Meglitinides | Biguanides | TZDs | AGIs | |
|---|---|---|---|---|---|
| Double combination therapy option* | ✓ | ✓ | |||
| Double combination therapy option† | ✓ | ✓ | |||
| Double combination therapy option | ✓ | ✓ | |||
| Double combination therapy option | ✓ | ✓ | |||
| Double combination therapy option | ✓ | ✓ | |||
| Double combination therapy option | ✓ | ✓ | |||
| Triple combination therapy option | ✓ | ✓ | ✓ | ||
| Triple combination therapy option | ✓ | ✓ | ✓ | ||
| If therapeutic goals are not met using the above combinations; switch to insulin with or without oral agent. | |||||
| *Available as Glucovance (metformin/glyburide) or as Metaglip (metformin/glipizide) | |||||
| † Available as Avandamet (rosiglitazone/metformin) | |||||
Non-sulfonylurea secretagogues
Like sulfonylureas, the non-sulfonylurea secretagogues (non-SU), repaglinide and nateglinide, stimulate beta cells to increase insulin secretion. However, the non-SU agents mediate their action through a different, adjacent site on the “sulfonylurea receptor.” Comparatively, the non-SU agents have a faster onset of action (20 minutes), shorter half-life (about 1.0–1.5 hours), and greater effects on postprandial glucose excursions than do sulfonylureas.20 In contrast to the sulfonylureas, the extent of insulin release with non-SU agents is glucose dependent, and therefore they may have less risk of hypoglycemia several hours after meals.15
A group of metabolic abnormalities that increase cardiovascular risk has been recognized since 1988 and has been given many names—Syndrome X, insulin resistance syndrome, dysmetabolic syndrome, The Deadly Quartet.73 The National Cholesterol Education Program Adult Treatment Panel III recently recodified this syndrome as shown below. The principles for diet and exercise discussed in this article also apply to the goals of reducing obesity and physical inactivity in the metabolic syndrome, and preliminary data suggest a reduction in the risk for type 2 diabetes (NNT per year=27; P=.000174) and for cardiovascular disease.75
| Risk factor | Defining level |
|---|---|
| Abdominal obesity | Waist circumference |
| Men | >102 cm (>40 in) |
| Women | >88 cm (>35 in) |
| Triglycerides | ≥150 mg/dL |
| HDL cholesterol | |
| Men | <40 mg/dL |
| Women | <50 mg/dL |
| Blood pressure | ≥130/85 mm Hg |
| Fasting glucose | ≥110 mg/dL |
Repaglinide lowers the A1c level by 1.7–1.9 percentage points, similar in efficacy to sulfonylureas. Nateglinide appears somewhat less efficacious and lowers A1c by 0.6–1.0 percentage points.15 Nateglinide was significantly less effective than glyburide at lowering A1c levels and the fasting plasma glucose in one 24-week study. Non-SUs added to sulfonylureas produce no additional benefit in glycemic control. The effect of non-SUs on microvascular or macrovascular endpoints is unknown.
Adverse effects. Hypoglycemia is the primary adverse effect of non-SUs. Confirmed hypoglycemia (plasma glucose <60 mg/dL) was observed in 2.4% of patients taking nateglinide compared with 0.4% of those receiving placebo. Mild or moderate hypoglycemia occurred in 16% of repaglinide patients, 20% of glyburide patients, and 19% of glipizide patients in one-year comparative studies. Further comparative studies are needed to determine if non-SUs produce significantly less hypoglycemia and weight gain than sulfonylureas.
Cost. Non-SUs must be dosed 3 times daily at the start of meals. One relative disadvantage is their increased cost compared with sulfonylureas.
Biguanides
The only biguanide marketed in the US is metformin. Its primary action is to inhibit hepatic glucose production and, to a much lesser extent, enhance insulin sensitivity in peripheral tissues.21 Metformin does not stimulate insulin secretion and does not cause hypoglycemia when used as monotherapy, but it can potentiate hypoglycemia in combination with insulin or insulin secretagogues.
Metformin is similar in efficacy to the sulfonylureas. It lowers A1c by 1.5–2.0 percentage points and fasting plasma glucose by 60–80 mg/dL. Its antihyperglycemic efficacy is independent of patient age, duration of diabetes, or BMI.22
In the UKPDS 34 study, a subgroup of obese patients was randomized to receive intensive control (group 1, metformin; group 2, a sulfonylurea or insulin) or conventional diet therapy (group 3). Despite a similar reduction in the A1c level between the 2 intensive-treatment groups, patients treated with metformin had a 32% reduction for any diabetes-related endpoint (95% CI, 13–47; P=.002), 43% fewer diabetes-related deaths (95% CI, 9–63; P=.017), and a 36% reduction in all cause mortality, compared with the diet therapy group (95% CI, 9–55; P=.011).23
Metformin also showed significant benefit when compared with patients receiving sulfonylurea or insulin (group 2). The absolute risk of any diabetes endpoint was 29.8 vs. 40.1 (events per 1000 patient-years; P=.0034), all-cause mortality (13.5 vs 18.9; P=.021), and stroke (3.3 vs 6.2; P=.032), respectively, for metformin vs sulfonylurea or insulin (group 2). Thus, metformin is the only oral hypoglycemic agent proven to reduce macrovascular risk in overweight patients with type 2 diabetes. For perspective, in overweight patients, metformin significantly reduced all-cause mortality (NNT per year=141; 95% CI, 115–183; P=.011), and any diabetes-related outcome (NNT per year=74; 95% CI, 63–90; P=.0023), compared with diet alone.23,24
