Treating type 2 diabetes: Targeting the causative factors
Physical activity: a little goes a long way
A regular physical activity program is recommended for all patients with diabetes who are capable of participating (SOR: B).7 It improves blood glucose control, reduces cardiovascular risk factors, aids weight loss, and enhances well being.7 A recently published prospective cohort study showed that walking at least 2 hours a week was associated with a 39% lower all-cause mortality (hazard rate ratio [HRR], 0.61; 95% CI, 0.48–0.78) and a 34% lower cardiovascular mortality (HRR, 0.66; 95% CI, 0.45–0.96) across a diverse spectrum of adults with diabetes. The NNT (to prevent 1 death per year) is 61 for patients who walk at least 2 hours/week.14
In prescribing a physical activity plan for a patient, consider cardiovascular disease risk factors or complications to minimize the risk of untoward events. Micro- and macrovascular disease are of course prevalent among persons with diabetes, often resulting in functional limitations that make exercise more difficult.
Other priorities
Other recommended components of care include daily aspirin use, foot care exams, tobacco cessation, pneumococcal and influenza vaccinations, and an annual dilated retinal exam.
Pharmacologic Therapy
The coexisting defects in type 2 diabetes mellitus are as follows:
- resistance to insulin action in muscle
- defective pancreatic insulin secretion
- unrestrained hepatic glucose production, aggravated by increased lipolysis in adipose tissue.
Drug therapy is aimed at each of these defects, and also at reducing carbohydrate absorption in the small intestine (Figure 1). As far as antihyperglycemic effect is concerned, no one category of antidiabetic agent is favored over another.15 Except for nateglinide and α-glucosidase inhibitors (AGIs), each of the drug categories leads to a similar reduction in A1c.16 However, patient characteristics may lead to selection of a particular agent. Table 2 summarizes oral treatment options, their relative advantages and costs.
FIGURE 1
Drug therapies for coexisting defects in type 2 diabetes
TABLE 2
Pharmacologic treatments for type 2 diabetes: monotherapies
| Target population | Advantages | Disadvantages | Dosing | Cost* |
|---|---|---|---|---|
| Sulfonylureas | ||||
| Recent type 2 DM diagnosis | Rapid FPG reduction | Weight gain | Glyburide: 1.25–20 mg once or twice daily (micronized, 0.75–12 mg once or twice daily) | $22.80 (5 mg, #120) |
| Type 2 DM <5 years duration | Low cost | Increased risk of hypoglycemia | Glipizide: 2.5–40 mg once or twice daily (extended-release, 2.5–20 mg once daily) | $14.66 (10 mg, #120) |
| Glimepiride: 1–8 mg once daily | $51.98 (10 mg, #60) | |||
| $57.98 (4 mg, #60) | ||||
| Non-sulfonylurea secretagogues (meglitinides) | ||||
| Recent type 2 DM diagnosis | Reduced risk of hypoclycemia | Higher cost | Nateglinide: 60–120 mg 3 times daily | $85.99 (120mg, #90) |
| Elevated PPG | Short-acting | Frequent dosing | Repaglinide: 0.5–4 mg 3 or 4 times daily | $218.06 (2 mg, #240) |
| Meal-adjusted dosing | ||||
| Biguanides | ||||
| Overweight/obese | No weight gain | GI side effects | Metformin: 500–1000 mg 2 or 3 times daily | $77.99 (850 mg, #90) |
| Insulin resistant | Reduced risk of hypoglycemia | High cost | Metformin XR: 1000–2000 mg once or twice daily | $89.98 (500 mg, #120) |
| Rare lactic acidosis | ||||
| TZDs | ||||
| Insulin resistant | Reduced amount of insulin | High cost | Rosiglitazone: 4–8 mg once or twice daily | $135.99 (8 mg, #30) |
| Overweight/obese | Reduced risk of hypoglycemia | Weight gain | Pioglitazone: 15–45 mg once daily | $153.99 (45 mg, #30) |
| Slow onset of action | ||||
| Liver toxicity | ||||
| AGIs | ||||
| Elevated PPG | Reduced risk of hypoglycemia | High cost | Acarbose: 50–100 mg 3 times daily | $67.99 (100 mg, #90) |
| Contraindications to other agents | Non-systemic action | GI side effects | Miglitol: 50–100 mg 3 times daily | $66.99 (100 mg, #90) |
| *Drug costs for 30 days’ supply of maximum daily dosage. From www.drugstore.com, December 2003. | ||||
| DM, diabetes mellitus; TZD, thiazolidinediones; AGT, a-glucosidase inhibitors; FPG, fasting plasma glucose; PPG, postprandial glucose; GI, gastrointestinal | ||||
Sulfonylureas
Sulfonylureas directly increase insulin secretion by binding to the sulfonylurea receptor on pancreatic beta cells; they provide a relatively quick onset of action. First-generation sulfonylureas (eg, tolbutamide, chlorpropamide) and second-generation sulfonylureas (eg, glyburide, glipizide, glimepiride) are equivalent in their maximum hypoglycemic effect.17
Second-generation agents are used more commonly than first-generation. They all contain the sulfonylurea moiety, but different chemical substitutions in the basic molecule change pharmacokinetics, resulting in different durations of action.17 Second-generation agents are probably safer than first-generation drugs, being less likely to cause hyponatremia, disulfiram-like reactions, or prolonged hypoglycemia.18
At maximal doses, sulfonylureas lower A1c levels by 1–2 percentage points and fasting plasma glucose concentrations by 60–70 mg/dL;15 however, the glucose lowering effect typically plateaus after half the maximal recommended dose is reached. Sulfonylureas have no consistent effect on dyslipidemia. In UK Prospective Diabetes Study (UKPDS) 33, though improved glycemic control with sulfonylureas (or insulin) led to a 25% reduction in microvascular endpoints (mostly less retinal photocoagulation) (P<.01), sulfonylureas (or insulin) did not significantly reduce death or all-cause mortality compared with diet treatment.2
Adverse effects. The primary adverse effects of sulfonylureas are weight gain and hypoglycemia. In UKPDS 33, weight gain at 10 years was 2.6 kg (99% confidence interval [CI], 1.6–3.6) with chlorpropamide and 1.7 kg (99% CI, 0.7–2.7) with glyburide, compared with patients receiving diet therapy (each P<.001).2 In the same study, the rate of major hypoglycemic episodes (third-party help or medical intervention necessary) while on therapy was 0.4%/year for chlorpropamide and 0.6%/year for glyburide, compared with 0.1%/year for diet.
