Insulin therapy in type 2 diabetes mellitus Dr . Ghadiri , MD Assistance professor of endocrinology ShahidSadoughi University of Medical Sciences
The importance of glycemic control in minimizing complications related to diabetes has been well established in type 1 diabetes . • United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that strict glycemic control in patients with type 2 diabetes results in a similar reduction in risk of microvascular disease .
Normoglycemia is now the goal for many patients with type 2 diabetes. • However, target C levels in patients with type 2 diabetes should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia.
Initial therapy should begin with diet, weight reduction, and exercise, which may induce normoglycemia if compliance is optimal. • Metformin therapy may be initiated, concurrent with lifestyle intervention, at the time of diabetes diagnosis.
Oral agents become less effective as beta cell function declines. The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including insulin, or to switch to insulin. • There is no consensus on which option is most effective. • However, insulin is the preferred second-line medication for patients with A1C >8.5 percent or with symptoms of hyperglycemia despite metformin titration.
NORMAL PATTERNS OF INSULIN SECRETION • Insulin is secreted in a pulsatile manner; pulses occur under basal conditions and in response to meals . • Basal insulin secretion represents approximately 50 percent of 24-hour insulin production, with the remainder accounted for by prandial (mealtime) excursions.
Basal Insulin In person without diabetes, the pancreas delivers a small amount of insulin continuously to cover the body’s non-food related insulin needs.
Bolus Insulin The amount of insulin required to cover the food you eat. Rapid-acting or Short-acting insulin works as a Bolus Insulin
Intensive insulin therapy has been used to describe complex regimens that separate basal insulin delivery (given as one to two daily injections of intermediate or long-acting insulin) with superimposed doses of short or rapid-acting insulins three or more times daily.
INSULIN PREPARATIONS In type 2 diabetes, insulin is generally provided in two ways: • Basal supplement to suppress hepatic glucose production and maintain near normoglycemia in the fasting state. • Pre-meal bolus dose of short-acting or rapid-acting insulin to cover the extra requirements after food is absorbed.
For many patients with type 2 diabetes, a basal supplement is often adequate for good glycemic control as endogenous insulin secretion will control the post-prandial excursions. • Some patients with type 2 diabetes will require additional premeal boluses, similar to treatment for type 1.
Premixed insulin preparations • Most premixed (biphasic) preparations contain an intermediate acting insulin and either a short or a rapid-acting insulin. • Some patients who require pre-meal insulin in addition to basal insulin prefer premixed insulins for convenience.
Premixed preparations offer little glycemic advantage compared with adequately titrated basal and bolus insulin . • In a meta-analysis of trials comparing rapid-acting/intermediate premixed insulin preparations with other treatments (premixed regular/NPH insulin, long-acting insulin, and non-insulin agents), premixed rapid-acting preparations were similarly effective in reducing A1C levels as premixed regular insulin preparations .
Compared with other insulin therapy (long-acting or regular/NPH mix), premixed rapid-acting insulin preparations were more effective in reducing postprandial blood glucose levels but less effective in reducing fasting blood glucose. • Premixed rapid-acting preparations were more often associated with minor hypoglycemia and weight gain than long-acting insulin or oral agents.
Premixed insulin preparations are sometimes used in type 2 diabetics, but we almost never use them in patients with type 1 diabetes. • For patients with type 2 diabetes who require prandial insulin, the goal is to adjust the dose of fast-acting insulin immediately prior to a meal, and therefore, we prefer to keep basal and premeal insulin injections separate and adjust them independently.
COMBINATION ORAL AGENT AND INSULIN THERAPY • Patients with persistent hyperglycemia despite oral hypoglycemic therapy may add insulin to oral medication or may stop the oral drug(s) and begin insulin. • The rationale for combination oral hypoglycemic drug and insulin therapy is that, by suppressing hepatic glucose production, the patient can retain the convenience of oral agents, while minimizing total insulin requirements .
Many studies have shown that glycemia improves with insulin combination therapy . • In some studies, target A1C goals (≤7 percent) were achieved in 60 to 70 percent of subjects .
Choice of insulin • When insulin is combined with oral agents, a basal (long- or intermediate-acting) rather than a short-acting premeal (prandial) insulin is a reasonable first choice. • The addition of basal insulin will improve nocturnal and fasting blood sugar, whereas premeal bolus insulin will decrease postprandial glucose excursions.
Basal insulin • While intermediate-acting NPH insulin has been used commonly at bedtime to supplement oral hypoglycemic drug therapy, longer acting insulins, such as insulin glargine (once daily) and detemir (once or twice daily), added to oral agents are equally effective for reducing A1C values and may cause less nocturnal hypoglycemia.
In contrast to NPH, the time-action profile for insulin glargine has virtually no peak ,which makes it an acceptable basal insulin preparation for intensive insulin therapy.
Insulin detemir: Long-acting insulin analog; a fatty acid side chain that allows albumin binding results in prolongation in action. However, its duration of action appears to be substantially shorter than that of insulin glargine .
Meta-analyses of trials in patients with type 2 diabetes comparing once-daily insulin glargine or detemir to once or twice-daily NPH insulin report similar glycemic control between groups . • Insulin glargine and detemir may have some relatively modest clinical advantages over NPH (less symptomatic and nocturnal hypoglycemia) with the important disadvantage of high cost.
Premeal (prandial) bolus insulin • For patients with type 2 diabetes, a basal supplement is often adequate for good glycemic control, but for others, premeal (prandial or preprandial) boluses are necessary as they are in type 1 diabetes.
The newer rapid-acting insulins may have a minor glycemic advantage over short-acting (regular) insulin in patients with type 1 diabetes, but they do not have a clinically significant advantage in patients with type 2 diabetes . • No significant differences were seen in serum A1C concentrations or the number of hypoglycemic episodes.
However, the ability to inject the rapid-acting insulins immediately before meals, as opposed to the 30 to 45 minutes before the meal recommended for short acting insulins, may provide improved convenience for patients.
Comparison of insulin regimens • A number of randomized trials have evaluated different insulin regimens in patients with type 2 diabetes. • These trials primarily used glycemic control as the endpoint; data are more limited on cardiovascular outcomes.
Basal versus prandial • Both basal and prandial regimens are similarly effective in reducing A1C concentrations when insulin doses are aggressively titrated to achieve glycemic goals.
This was illustrated by a randomized trial of once daily insulin glargine versus prandial insulin lispro in 415 patients who were inadequately controlled with metformin and a sulfonylurea . • There were similar improvements in A1C and target A1C concentrations between 6.5 and 7.0 percent were achieved by 27 and 30 percent of subjects, respectively. Basal insulin was associated with greater patient satisfaction and less hypoglycemia.
Basal or prandial versus premixed • Premixed insulin regimens with fixed combinations of short or rapid acting insulin with long or intermediate acting insulin claim to provide two peaks of insulin activity from just one injection, although in practice the peaks from the rapid acting and intermediate acting insulins tend to merge together and form a single peak of insulin action.
In a three-year trial, 708 patients with type 2 diabetes who were suboptimally controlled with metformin and a sulfonylurea were randomly assigned to premixed biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily) .There was no difference in median A1C levels among the three groups, but significantly more patients in the basal and prandial groups achieved an A1C level of ≤6.5 percent than in the biphasic premixed group . • Patients in the basal group had the fewest episodes of hypoglycemia.
Conclusion : Whether a basal or a prandial (premeal) bolus strategy is more effective in improving important diabetes endpoints (microvascular and macrovascular complications) remains uncertain. In the absence of such data, we prefer initiating basal insulin, rather than prandial insulin, in patients who are poorly controlled on oral agents . For patients who require prandial insulin, we prefer to keep basal and prandial insulin injections separate and adjust them independently.
Insulin dose • Basal • Bedtime dose of NPH, detemir, or glargine insulin is being added to oral drug therapy:10units or 0.2 units per kg (taken at 10:00 PM). • Fasting blood glucose (FBG) should be measured every day. An increase of 2 to 4 units in the bedtime insulin dose should be made periodically (approximately every three days) if the mean FBG is above 130 mg/dLduring this time .
In this way, the bedtime insulin dose can be titrated over a period of several weeks or months. If fasting glucose levels are very elevated (>250 mg/dL), or if a patient is known to be very insulin resistant, initial doses can be higher and titration more aggressive.
Bolus • If premeal bolus insulin needs to be added, the optimal dose depends upon many factors, including current and target blood glucose values, carbohydrate content of the meal, and activity. • A typical starting dose is approximately 4 to 6 units. The dose can be increased by 2 to 3 units every three days until the postprandial blood glucose target is achieved.
Optimal timing of insulin dose • For patients with type 2 diabetes on combination therapy (oral hypoglycemics and once-daily insulin), the optimal timing of the insulin dose depends in part upon the type of insulin. NPH insulin may be most effective if given at bedtime . • Bedtime NPH : Less weight gain
In contrast, a morning rather than a bedtime dose of insulin glargine may provide better glycemic control in patients with type 2 diabetes who are also treated with an oral agent. • Nocturnal hypoglycemia was less frequent with morning and bedtime insulin glargine than with bedtime NPH.
For patients with type 2 diabetes taking an oral hypoglycemic agent, the optimal timing is once-daily NPH or detemir at bedtime or once-daily insulin glargine in the morning or bedtime.
SWITCHING TO INSULIN MONOTHERAPY • Patients with persistent hyperglycemia despite oral hypoglycemic therapy may stop the oral drug and begin insulin monotherapy. • This approach is cheaper than combined therapy (although generic metformin is relatively inexpensive), but results in more weight gain and more episodes of hypoglycemia.
Starting dose • The initial dose of insulin in patients with type 2 diabetes switching to monotherapy is similar to the starting dose described above for patients adding insulin to oral hypoglycemic therapy .
Among patients who are taking insulin and have A1C values above the desired target, diet and exercise patterns should first be reviewed. Insulin doses should then be adjusted to achieve target levels of glycemia. • Patients should measure blood glucose two to four times daily and should only reduce their insulin dose if hypoglycemia develops.
In general, dietary indiscretion and/or inadequate doses of insulin underlie the apparent failure of many patients treated with insulin regimens. Daily insulin doses typically exceed 65 to 100 units per day, and may sometimes be much higher, before obese type 2 diabetic patients can achieve near-normal glycemia.
Once-daily regimens • For patients receiving insulin monotherapy, a once-daily dose of intermediate- or long-acting insulin is sometimes sufficient . • As an example, insulin glargine is effective when used alone for once-daily therapy in patients with type 2 diabetes and may be associated with less nocturnal hypoglycemia and less weight gain than NPH .
However, serum insulin concentrations over a 24-hour period may be more stable in patients taking two doses daily, when the insulin preparation is NPH or detemir.
Twice-daily regimens • If the goal is control of persistent hyperglycemia with a regimen that is simple, then twice-daily NPH insulin will be effective in many patients. If excessive postprandial rises in blood glucose are a concern, then a short- or rapid-acting insulin must be added. • Injection of regular plus NPH insulin before breakfast and before dinner results in four peaks of insulin action, covering the morning, afternoon, evening, and overnight . • However, the peaks tend to merge. Furthermore, with the common practice of drawing up both insulin preparations in the same syringe, serum insulin peaks become less distinct.
Intensive insulin • Use of an intensive insulin regimen (similar to that used in T1DM) results in higher serum insulin concentrations and better glycemic control than that achieved with either an oral drug or conventional insulin therapy alone . • A potential problem is the weight gain (8.7 kg in one study) that can occur with intensive regimens that achieve near normal glycemia. • This weight gain may in some instances result in partial noncompliance with therapy, particularly in women.
INSULIN AS INITIAL THERAPY • An alternative that may be beneficial, but is not widely used, is a brief period (two to four weeks) of intensive insulin treatment at the onset of type 2 diabetes .By inducing near normoglycemia with intensive insulin therapy, both endogenous insulin secretion and insulin sensitivity improve . • The improvement in insulin secretion is presumably due to the elimination of the deleterious effects of hyperglycemia on beta cell secretory function, and in some patients, it results in better glycemic control that can then be maintained with diet and exercise for many months thereafter.
Insulin should be particularly considered for patients presenting with A1C >10 percent, fasting plasma glucose >250 mg/dL, random glucose consistently >300 mg/dL, ketonuria, or with unplanned weight loss in association with hyperglycemia.