Treating type 2 diabetes: Targeting the causative factors

Cost. TZDs are expensive relative to other hypoglycemic agents.

α-glucosidase inhibitors

The α-glucosidase inhibitors (AGIs), acarbose and miglitol, act through competitive, reversible inhibition of membrane-bound intestinal α-glucosidase, which hydrolyzes complex carbohydrates to glucose and other monosaccharides. This inhibition delays glucose absorption and decreases postprandial hyperglycemia.³⁷ Thus, they have a nonsystemic mechanism of action.

These agents cause a modest reduction in the A_1c level (0.5–1.0 percentage points) and are thus less effective than sulfonylureas, metformin, or TZDs. They do not reduce fasting plasma glucose levels, but reduce postprandial hyperglycemia by 50 mg/dL.³⁸ No long-term studies have evaluated whether AGIs reduce diabetes-related macrovascular or microvascular outcomes.

Adverse effects. While AGIs are virtually free of serious toxicities, patient tolerability can be a problem due to adverse gastrointestinal effects. In indirect comparisons from placebo-controlled trials, patients treated with miglitol and acarbose commonly reported abdominal pain (11.7%, 19%), diarrhea (28.7%, 31%), and flatulence (41.5%, 74%), respectively. Systemic accumulation of AGIs has been shown to increase in proportion to the degree of renal insufficiency, and their use is not recommended for patients with serum creatinine >2.0 mg/dL. However, whether such patients are at greater risk of any toxicity is unknown. Acarbose at doses above 100 mg 3 times daily has been associated with elevated serum transaminase levels; however, this risk appears negligible at standard doses.

Insulin

Insulin is the oldest therapy for diabetes, and it has no upper dose limit.³⁹ It increases insulin levels and can reduce A_1c levels by 1.5 to 2.5 percentage points. Though half of diabetes patients need insulin eventually for optimal control, historically it has been introduced late in the disease process unless patients have severe hyperglycemia (fasting blood sugar >350 mg/dL) or ketonuria.³⁸ However, it is effective in gaining initial control, decreasing gluconeogenesis and increasing glucose uptake. Disadvantages are weight gain, hypoglycemia, and patient reluctance to give injections.

When insulin is indicated. Patients who exhibit persistent hyperglycemia despite oral hypoglycemic therapy may stop the oral drug(s) and begin insulin. By combining insulin with oral therapy, lower insulin doses may be used to achieve desired control vs using insulin alone.⁴⁰ For some patients a basal supplement of insulin may be sufficient and can be given as a single dose at bedtime, without an oral hypoglycemic drug.⁴¹

Insulin regimens. Various insulin regimens are available: very rapid acting (lispro and aspart), rapid acting (regular), intermediate acting (isophane insulin [NPH] and lente) and very long acting (ultralente and glargine). Glargine insulin (Lantus) has more predictable absorption than NPH, lente, and ultralente. Lantus, compared with NPH, has been associated with less nocturnal and postprandial hypoglycemia.^38,42,43 This is consistent with the peakless and longer duration of glargine compared with NPH.⁴⁴ A recent randomized controlled trial demonstrated that morning insulin glargine lowered A_1c levels more than a bedtime dose of NPH (–1.24 vs –0.84; 95% CI, 0.23%–0.58%) or a bedtime dose of glargine (–1.24 vs –0.96%; 95% CI, 0.11%–0.46%).⁴⁵ Glargine’s only relative disadvantage is increased cost.

Combination products. Combination insulin options are 70 NPH/30 regular, 50 NPH/50 regular, and 75 lispro protamine/25 lispro. Many combinations of insulin regimens have been used successfully. The typical range of insulin needed for monotherapy is 0.4–1 U/kg/d. Once-daily injection of intermediate acting or long acting insulins at bedtime or before breakfast, once-daily or twice-daily combinations of intermediate and rapid acting insulins, and more complex regimens have been used to good effect.

Using prandial insulin at each meal with separate basal insulin adds flexibility to meal times and doses administered.⁴³ With multiple-dose intensive insulin therapy, a basal dose suppresses hepatic glucose output and the bolus doses enhance postprandial glucose uptake. This intensive insulin treatment reduces mortality among critically ill patients in surgical intensive care units and for those with acute myocardial infarction.^46,47 An algorithm for using progressive therapy in diabetes mellitus is shown in Figure 2.⁴⁸

FIGURE 2
ADA recommendations for the treatment of type 2 diabetes

Combination Therapy

Over time glycemic control becomes more difficult, even with maximum monotherapy for patients with healthy lifestyles. It was shown in UKPDS 49 that monotherapy with sulfonylurea, metformin, or insulin eventually fails in most cases—by 3 years after diagnosis, about 50% of patients need more than monotherapy; 75% by 9 years.⁴⁹ In UKPDS 33, the median A_1c level increased steadily over 10 years with both conventional therapy and intensive therapy (Figure 3).²

Several options are available when monotherapy fails. Based on expert opinion, the principle is to combine drugs with different mechanisms of action to achieve an additive effect for glycemic control. Combination products may simplify the treatment regimen and improve adherence. In many instances, they may also cost less.⁵⁰