Insulin Analogs or Premixed Insulin Analogs in Combination With Oral Agents for Treatment of Type 2 Diabetes

Philip Levy, MD, FACE

Disclosures

April 16, 2007

How to Initiate, Integrate, Titrate, and Select Insulin Therapy

The clinical evidence described previously supports the view that ADA and AACE targets for patients with type 2 diabetes who are failing oral therapy can be achieved with basal or premixed insulin analogs plus OADs (see subsequent discussion). This approach to insulin therapy is easy to initiate, adjust, and intensify,[72] and consistent with the ACE/AACE road map to achieve glycemic control (A1C ≤ 6.5%). The road map recommends the following steps in patients who have not achieved A1C goal on a single oral drug: combination therapy with oral agents, addition of an incretin mimetic (eg, exenatide), or addition of basal or premixed insulin to oral treatment. Patients not achieving A1C goal on combination treatment should have basal insulin added if FPG is elevated, bolus insulin added if PPG is elevated, and premixed insulin or basal-bolus insulin therapy if both FPG and PPG are above targets.[18]

Many who start insulin therapy may remain on one or more oral drugs for some time. Metformin and/or a thiazolidinedione are most suitable for combining with premixed insulin analogs or with rapid-acting insulin analogs. Oral insulin secretagogues are not synergistic with rapid-acting insulin[11]; however, a secretagogue can be continued if using a basal insulin analog. Exenatide is not indicated for use in combination with insulin at this time.

Basal-bolus therapy with multiple daily injections (MDI) or an insulin pump is generally considered to be the most physiologic approach to insulin therapy.[43,54] With MDI therapy, basal insulin is injected once or twice per day and short- or rapid-acting prandial insulin is administered with each meal. This approach has been shown to be highly effective for the achievement of tight control over both FPG and PPG, and is now generally viewed as the optimal regimen for insulin therapy for patients with diabetes.[50,73] While highly effective and generally well tolerated, this approach may not be suitable for many patients.[43] MDI therapy requires 4 or more injections per day, along with associated blood glucose measurements and comprehensive education including carbohydrate counting. This approach also involves considerable teaching time for healthcare providers.

Individualized blood glucose targets should be established for each patient and should be aimed at decreasing the risk for hypoglycemia while maintaining good glycemic control. The starting regimen is determined primarily by the degree of hyperglycemia and the current A1C value. Simple dosing algorithms for a basal analog ( Table 4 )[23] and premixed insulin analog ( Table 5 )[43] have been developed.

Despite which algorithm is used, the dose is titrated based on results from self-monitoring of fasting plasma glucose until glycemic goals are met.[43,44] If treatment goals are not achieved within 1 week, an additional 1 to 3 units for every 50 mg/dL that pre-meal glucose exceeds the target level should be added. Doses should be reduced by a similar amount if glucose levels are too low or the patient experiences hypoglycemia.[43,44] Intensification of insulin therapy may not be appropriate for all patients. Those with a short life expectancy, comorbidities, advanced complications of diabetes, the very young, or those who are prone to severe hypoglycemia represent examples of patients in whom moderate rather than tight glycemic control may be appropriate.[11]

Insulin analogs are more expensive than human insulin preparations, presumably because they represent a technological improvement over older insulin formulations. Out-of-pocket costs vary from formulation-to-formulation, and even the cost of the same analog may vary by pharmacy, insurance plan, and reimbursement factor. The 2- to 3-fold higher cost of an insulin analog compared to a human insulin may represent a barrier for some patients. For others, the improved predictability, tolerability, and flexibility of analogs may make the added expense more acceptable. As such, better adherence should ensue, and fewer complications may translate to cost benefits and fewer out-of-pocket medical expenses over the long-term.[74]

To choose from among the various insulin analogs, physicians should begin by deciding which of the 3 approaches to therapy suits the particular patient best. For example, if a basal insulin is to be added to oral therapy, how does one choose between insulin glargine and insulin detemir? Both have similar pharmacokinetic and time-action profiles, provide similar reductions in A1C, and are associated with a lower risk of hypoglycemia than NPH insulin. In virtually all clinical trials in which insulin detemir has been studied,[52] it has been associated with less weight gain than NPH. This effect has not consistently been observed with insulin glargine,[51] and for patients concerned with weight gain, insulin detemir may thus be preferred.

If a rapid-acting insulin analog is to be added to mealtimes, or used in basal-bolus therapy, all 3 available formulations (aspart, lispro, glulisine) appear to have similar characteristics. Similarly, for patients who prefer the simplicity and convenience of premixes, BIAsp 30, lispro 75/25 (or 50/50), individual patient preference, lifestyle, or the availability of the particular premix in a particular pen device might guide the choice.

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