Insulin treatment for type 2 diabetes: When to start, which to use
ABSTRACTIn type 2 diabetes mellitus, oral hypoglycemic agents and analogues of glucagon-like peptide-1 provide adequate glycemic control early in the disease. Insulin therapy becomes necessary for those with advanced disease. Further, some experts recommend electively starting insulin therapy in early diabetes. This review addresses practical approaches to insulin therapy, particularly when it is indicated and which regimen to use.
KEY POINTS
- Whether to start insulin therapy and which regimen to use depend on a number of factors, including the patient’s acceptance and willingness to adhere to the therapy.
- A common way to start is to add a once-daily dose of a long-acting insulin at bedtime (basal insulin) to the patient’s antidiabetic regimen.
- Basal regimens do not control postprandial hyperglycemia very well. Another option is to take a long-acting (basal) insulin along with a rapid-acting (prandial or bolus) insulin before meals. Multiple formulations of premixed insulins are available and are convenient to use among new users.
- Basal-bolus regimens, which involve injections of rapid-acting insulin before meals and long-acting insulin at bedtime, are gaining popularity. Their cost and the number of injections may affect patient acceptance of this treatment.
The glycemic goal should be individualized
The key issue is glycemic control. If glycemic control is worsening or if the hemoglobin A1c level remains above the goal, then the treatment strategy should be readdressed.
In general, one should try to achieve the best possible glycemic control with the few est adverse effects. Adequate dietary management with a regular meal schedule and predictable carbohydrate intake for each meal helps to avoid or at least minimize the two most important adverse effects of insulin, ie, weight gain and hypoglycemia.
For most patients, I believe a goal hemoglobin A1c level of less than 7% is reasonable.2 For others, a less stringent goal might be more appropriate, such as 7.5%. Several factors affect this decision, including whether the patient is willing to follow a complex insulin regimen (such as a basal-bolus regimen), his or her work schedule, other lifestyle factors, the duration of diabetes, the type or types of insulin used, coexisting medical conditions, the frequency of hypoglycemia, unawareness of hypoglycemia, age, prognosis, life expectancy, and cost.5
If hyperglycemia is severe (Table 1),2 the goal might not be clear when insulin therapy is started. It should become obvious with ongoing follow-up.
Previously untreated patients presenting with severe hyperglycemia are a heterogeneous group. Many of them have had diabetes for a relatively short time and were recently diagnosed. These patients are likely to safely achieve near-normal glycemic control. Some of them might be adequately treated with oral hypoglycemic agents; if insulin is used, transitioning from insulin to oral hypoglycemic agents may be feasible.2
Some untreated patients may have had diabetes for several years and have advanced disease and therefore might be more difficult to treat. Only 21 (57%) of 37 previously untreated patients intensively treated with insulin reached the goal fasting glucose level of less than 126 mg/dL in one study.6 The only way to evaluate the feasibility of achieving near-normal glycemia safely is by following the patient’s progress over time.
The patient’s glycemic goal should be reevaluated periodically and may need to be adjusted over time, based on changes in any of the factors discussed above.
Risk of hypoglycemia
The goal should be looser in difficult-to-treat patients, ie, those with frequent hypoglycemia and decreased awareness of hypoglycemia.
Patients with advanced diabetes whose glucose levels continue to fluctuate widely after lifestyle management and the insulin regimen have been addressed should also have a looser goal. These fluctuations of glucose levels are surrogate markers for the degree of insulin deficiency. Attempting to achieve near-normal glycemic levels in this situation would be associated with a higher risk of hypoglycemia.
A higher risk of hypoglycemia and its complications (eg, falling and accidents, especially among operators of heavy machinery, construction workers, and drivers) is another reason for adopting a relaxed goal of glycemic control.
ADDING BASAL INSULIN TO ORAL HYPOGLYCEMIC THERAPY
When glycemic control worsens or is not adequate despite the use of oral hypoglycemic agents, often the next step is to add basal insulin therapy, ie, once-daily doses of a long-acting insulin.
NPH, detemir, or glargine?
Most often, glargine or detemir (Levemir) insulin is used. Detemir can also be given twice daily if needed. If cost is a concern, neutral protamine Hagedorn (NPH, Humulin N, Novolin N) insulin once daily at bedtime or twice daily is a reasonable alternative.
Costs of basal insulins are $22 to $50 per 1,000-unit vial for NPH, $70 to $90 per 1,000-unit vial for detemir and glargine, and $170 to $200 for a box of five detemir or glargine pens (containing 1,500 units total). Complicating this issue, vials should not be used for more than 1 month, and thus, the cost of vials vs pens depends on dosage.
Detemir vs NPH. In a trial in patients with inadequately controlled type 2 diabetes who had never taken insulin before and who were taking one or more oral hypoglycemic drugs, the addition of detemir insulin once daily or NPH at bedtime resulted in similar improvements in hemoglobin A1c (a decrease of about 1.5%).10
Detemir had several advantages over NPH. First, the incidence of nocturnal hypoglycemia was 50% lower with detemir at bedtime than with NPH at bedtime, and 87% lower with detemir in the morning than with bedtime NPH.10 In another trial,11 the risk of hypoglycemia at any time of day was 47% lower with insulin detemir than with NPH, and the risk of nocturnal hypoglycemia was 55% lower.
The risk of nocturnal hypoglycemia is lower if detemir is taken in the morning than at bedtime, although the total frequency of hypoglycemic episodes is the same.10 Therefore, another decision after starting basal insulin, based on the patient’s glucose trends and frequency of hypoglycemic events, would be whether insulin should be taken in the morning or at bedtime.
The second advantage of detemir is that it causes less weight gain: 0.7 kg at 20 weeks with detemir at bedtime vs 1.6 kg with NPH at bedtime.10
Further, detemir insulin was associated with less within-subject variability in the fasting glucose level than with NPH when these insulins were used in a basal-bolus regimen.12
Hermansen et al11 found that if the dosage of basal insulin was aggressively increased, 70% of patients achieved a hemoglobin A1c target of less than 7% with either NPH or detemir insulin, with fewer hypoglycemic episodes in patients treated with detemir.
Therefore, adding basal insulin to oral therapy is adequate for many patients who are new to insulin. Many patients would need more, such as the addition of insulin before meals.
Glargine vs NPH. Compared with adding NPH, adding glargine to a regimen of oral hypoglycemic agents controls blood glucose levels better and with less fluctuation in glucose levels, a lower risk of hypoglycemia, and less weight gain.13–15 These results were the same when using glargine with either metformin13 or glimeperide (Amaryl).14
Glargine is usually given once daily at bedtime. One study suggested that giving it in the morning is more effective.14
Detemir vs glargine. Studies that compared detemir and glargine revealed more similarities than differences in their clinical benefits.16,17 Both preparations effectively lower glucose levels and improve quality of life.18
Titrating the insulin regimen is a key in achieving adequate glycemic control. This includes teaching patients how to adjust their insulin, for example by increasing the dosage of glargine or detemir by 2 units every 4 to 7 days until adequate glycemic control is achieved, unless hypoglycemia becomes a barrier.
