Rationale:

• Twice-daily intermediate-acting insulin or once-daily insulin glargine provides around-the-clock coverage for patients who no longer respond to sulfonylureas or other oral agents.
• Adding regular insulin in the morning should lead to peak action around lunchtime; in the evening, it should lead to peak action around bedtime.
• Pramlintide is an analog of the human β-cell hormone amylin, which can be given subcutaneously to patients on insulin to achieve optimal glycemic control.

Evidence:

• There is no documented advantage to multiple daily injections in patients with type 2 diabetes (116).
• Randomized controlled trials of different insulin dosing regimens demonstrate that insulin can reduce HbA_1c by 1% to 2%; there is minimal advantage to dosing insulin more than twice daily in patients with type 2 diabetes (116).
• In a 6-month study, 233 insulin-naïve patients with HbA_1c >8.0% taking metformin alone or in combination with other oral agents had their metformin dose adjusted up to 2550 mg/d before insulin therapy was initiated with 5 to 6 U biphasic insulin aspart 70/30 (contains 30% soluble insulin aspart and 70% insulin aspart crystallized with protamine) twice daily or 10 to 12 U glargine at bedtime and titrated to target blood glucose levels of 80 to 110 mg/dL by algorithm-directed titration. At study end, the mean HbA_1c value was lower in the biphasic insulin aspart 70/30 group than in the glargine group (6.91 vs. 7.41), and more patients taking biphasic insulin aspart 70/30 reached target HbA_1c of <7.0% (66% vs. 40%). Minor hypoglycemia episodes were greater in the biphasic insulin aspart 70/30 group than in the glargine group, as were weight gain (5.4 vs. 3.5 kg) and daily insulin dose (78.5 vs. 51.3). Thus, in subjects with poorly controlled type 2 diabetes taking oral agents, initiating insulin therapy with twice-daily biphasic insulin aspart 70/30 was more effective in achieving HbA_1c targets than once-daily glargine, although weight gain and insulin dose were higher (117).
• In a pooled analysis of data from two large, multicenter, randomized, placebo-controlled trials, the addition of pramlintide before meals in insulin-treated patients led to a greater reduction in HbA_1c of 0.43% and a concurrent decrease in weight of 2 kg as compared to placebo at week 26. Rates of hypoglycemia were similar in both groups. In other analyses, the above changes were seen in all ethnic groups, and the greatest weight loss occurred in those with a BMI >40 kg/m² who were on insulin and metformin. The most common adverse event reported with pramlintide treatment is transient nausea, which is usually mild to moderate and dissipates with continued treatment (118; 119; 120; 121; 122).

Comments:

• Lispro, aspart, and glulisine insulin are newer rapid-onset, shorter-acting forms of insulin that may be useful in managing postprandial hyperglycemia or when patients inject insulin immediately before meals (123; 124; 125).
• Combinations of protamine and lispro and aspart are also now available as biphasic insulin lispro 25/75 (25% soluble insulin lispro and 75% neutral protamine lispro) and biphasic insulin aspart 70/30 (contains 30% soluble insulin aspart and 70% insulin aspart crystallized with protamine). These new biphasic insulin analog combinations provide better postprandial glycemic control compared with 70/30 regular/NPH insulin in subjects with type 2 diabetes (126).
• Another option is insulin glargine, a long-acting insulin that is administered subcutaneously once daily (at the same time every day), which achieves similar levels of glucose control when compared to NPH but may result in less nocturnal hypoglycemia. It cannot be mixed with any other type of insulin and, in converting from NPH, a 20% initial reduction in number of units is required. It is currently significantly more expensive than other types of insulin (127; 128).
• The FDA has approved insulin detemir (rDNA origin) injection for once- or twice-daily subcutaneous administration in the treatment of adult patients with type 1 or type 2 diabetes mellitus who require basal insulin for the control of hyperglycemia. The formulation is active for up to 24 hours and has a relatively flat action profile. In a 26-week, multinational, open-label, parallel group trial, patients with type 2 diabetes who were treated with insulin detemir plus insulin aspart at meal times experienced comparable glycemic control but significantly lower within-subject variability and less weight gain compared to patients treated with NPH insulin and insulin aspart. In this study, insulin detemir was well tolerated and had a similar safety profile to NPH insulin (129).
• Pramlintide, an analog of the β-cell hormone amylin, decreases gastric emptying, prevents the postprandial increase in glucagon, and increases satiety, leading to decreased food intake and potential weight loss. It can also be given to patients taking insulin with metformin and/or a sulfonylurea and can be used in insulin-dependent patients with type 1 diabetes.
• In 2006, the FDA approved inhaled insulin (Exubera®) for the treatment of adult patients with type 1 and type 2 diabetes. However, due to poor patient acceptability and low sales volume, Pfizer withdrew the product in October 2007. The company stressed that there were no safety concerns with inhaled insulin.
• Due to the increased risk of weight gain, edema, and congestive heart failure in patients using maximum doses of a thiazolidinedione drug and insulin, consideration should be given to reducing the dose of the thiazolidinedione.