The Benefits Of Insulin Therapy

Despite the reservations of many practitioners about initiating insulin therapy, there should be no question about the ability of insulin to help patients with type

2 diabetes reach therapeutic goals. A number of studies have documented the success of progressive treatment regimens that include graduated insulin therapy (16,17). Obviously, recognition of a progressive |3-cell defect leads to the conclusion that exogenous insulin will be required when overall insulin secretion is inadequate to reach an HbA,c of 7.0%.

However, insulin has a number of other benefits that are important to understand. As blood glucose elevates due to failure of oral agent therapy or due to other factors such as an intercurrent illness, the elevated glucose levels create a vicious cycle often referred to as "glucotoxicity." This term applies to the ability of hyperglycemia to increase insulin resistance and to further inhibit p-cell function (18). Insulin therapy has proven to be the most predictable and rapid method of correcting the hyperglycemia and therefore overcoming the glucotoxicity. Accordingly, the doses of insulin required to attain the desired glucose reductions may be considerably higher than the doses required to maintain glucose goals later. In many cases in which insulin is used to control severe, symptomatic hyperglycemia at the time of diagnosis, oral agents can effectively replace insulin therapy after a period of glucose stabilization. Sometimes physicians ignore this possibility and patients remain on insulin indefinitely only because oral agent therapy was never attempted.

In type 2 diabetes, most obese patients experience significant elevations of fasting blood glucose. The postprandial glucose excursions are then added to this elevated baseline glucose. In many cases, early treatment with sulfonylureas will expose the tendency to maintain elevated fasting glucose levels despite the possibility of hypoglycemia at other times, such as before dinner. The underlying morning hyperglycemia is the result of excess hepatic glucose production during the night. Normally, insulin suppresses hepatic glucose production. In fact, exogenous insulin will reduce excess glucose production at doses that are significantly lower than those required to facilitate insulin-mediated glucose uptake in muscle tissue. Treatment with evening insulin is clearly the most targeted and effective method of reducing fasting blood glucose.

COMBINATION THERAPY WITH ORAL AGENTS AND INSULIN

The addition of insulin to sulfonylureas became popularized over a decade ago as clinical researchers began to better understand die pathophysiology of type 2 diabetes and also recognized the reluctance of patients and physicians to proceed to insulin therapy when indicated. The concept of BIDS (bedtime insulin, daytime sulfonylurea) developed from the knowledge that bedtime intermediate insulin could effectively reduce nocturnal hepatic glucose production and reduce glucotoxicity. The improved morning blood glucose levels then promote the daytime effectiveness of the sulfonylureas, including reduced postprandial glucose excur tX

sions. The simplicity of this evening insulin strategy is also an excellent transition to later, more complex insulin therapy. Patients need take the bedtime dose of NPH insulin only when they enjoy relative privacy, and they need focus on morning blood glucose monitoring only initially, since the method will not be successful until the fasting glucose is controlled. Also, hypoglycemia is also relatively unlikely to occur with this method.

Compared with regimens consisting of morning NPH with sulfonylureas, Regular and NPH insulin twice daily, or a basal-prandial insulin regimen, the BIDS approach demonstrated equal efficacy with less weight gain (19). Combined insulin-sulfonylurea therapy has been followed by evening insulin combinations with subsequently released classes of oral agents, including metformin and TZDs. A carefully designed study comparing evening insulin combinations with metformin, glyburide, combined glyburide and metformin, or a second morning insulin dose demonstrated the ability of the metformin-insulin combination to maximize glucose reductions with minimum weight gain (20). Of course, various combinations of oral agents are routinely used with evening insulin in the normal progression of therapy. These various combinations have not been individually evaluated.

INTENSIFIED INSULIN REGIMENS

Type 2 diabetes is not a homogeneous disease. For example, some individuals will have accelerated loss of insulin secretion and require multiple insulin injections within a few years. These patients are often of normal weight but have no evidence of type 1 diabetes. Nevertheless, their primary pathophysiological defect is related to insulin deficiency rather than insulin resistance. Many others will have a slowly progressive [3-celJ dysfunction that eventually results in severe insulin deficiency and the need for insulin. Because a larger number of individuals are developing type 2 diabetes at an early age, this latter segment of the population will also lead to the more frequent need for more complex insulin regimens. Twice-daily intermediate/Regular insulin dosing has been commonplace in treatment of type 2 diabetes. This regimen often implements premixed insulin twice daily for simplicity.

However, the trend now is toward more physiological insulin regimens, like those commonly used in type 1 diabetes. The most advanced scheme utilizing injectable insulin is frequently referred to as a "basal-prandial" or "basal-bolus" insulin regimen. These regimens are designed to simulate physiological insulin delivery as much as possible. They employ long-acting insulin in amounts necessary to suppress hepatic glucose production and provide the low levels of insulin needed during periods without food ingestion. Short-acting or very-short-acting insulins (analogs lispro and aspart) are then used to supply the insulin needed for food intake. If properly employed, this regimen offers increased lifestyle flex

ibility in addition to better consistency and possibly less hypoglycemia. Continuous subcutaneous insulin infusion (insulin pump) therapy is the most technologically advanced model of this approach but is not considered a standard option for type 2 diabetes at this time. Fortunately, after the struggle for many years with suboptimal long- and intermediate-acting "basal" insulins, the recent availability of the long-acting insulin analog glargine has greatly improved the practicality and simplicity of basaJ-prandial insulin therapy. Generally, the relative ratio of basal: prandial insuJin is close to 1:1 (prandial doses combined comprise about 50% of total daily insulin). Historically, more complex insulin regimens have carried an increased risk of hypoglycemia. This is not necessarily true for glargine—lispro or glargine-aspart regimens. Glargine has a 24-hour duration and is more consistently absorbed than other basal insulin options. It is usually administered once daily, at bedtime. The dose is titrated to attain morning glucose values under 120 mg/dl.

THE ROLE OF INSULIN IN TYPE 2 DIABETES TREATMENT PROGRESSION

Because type 2 diabetes is a progressive disease, the treatment strategy has evolved into a sequential intensification most often marked by addition of oral agents as needed to maintain glucose control goals. When appropriate combinations of oral agents fail, insulin is typically added. As shown in Table 2, unless initiated early because of severe hyperglycemia at diagnosis, insulin is most often introduced when two or three oral agents in combination have failed.

A significant decision point is noted at step 4 in the table. It is here that one must decide between adding a third oral agent, most often a TZD, or adding insulin. Although adding a TZD is reasonable, considering the role of insulin resistance in most cases of type 2 diabetes, this strategy is not as predictable as utilizing insulin in attempting to reach target glucose levels. When a TZD is added, one must be certain that an HbAlc of <7.0% is reached within 3 or 4 months. If this goal is not attained, one should change to insulin. Furthermore, the addition of insulin is generally more cost-effective in lowering blood glucose.

When adding evening NPH to a sulfonylurea and metformin, one should decrease the sulfonylurea to half the maximal dose (e.g., 4 mg glimepiride, 10 mg glipizide GITS, or 10 mg glyburide) if a larger dose had been used prior to tliis change. If glargine is used at bedtime, one should reduce the sulfonylurea to 25% of maximum dose. Because glargine will carry over a significant insulin effect before dinner, the sulfonylurea may require further reduction or may be eliminated.

Likewise, when triple oral agent therapy has been instituted but is no longer successful, insulin should be added to the three-drug regimen and the sulfonylurea

Table 2 Typical Progression of Type 2 Diabetes Therapy (Goal HbAlc 7.0%; therapeutic change point >7.0% x 2 (at 3-month intervals)

Primary

Alternatives

Step 1

Lifestyle change

Diet and exercise

If HbAlc < 8.0%

Go to Step 2

If HbA1c 8-9.5%

Go to Step 3 or 5

If HbAic > 9.5%

Step 2

Oral monotherapy

Pioglitazone, rosiglitazone,

Metformin or sulfonylurea

repaglinide, nateglinide

(acarbose, miglitol)

Step 3

Oral combination therapy

Add acarbose or miglitol

Add metformin, SU, TZD, Re-

paglinide, or nateglinide

Step 4

Three-agent therapy

Add third drug with different

mechanism

e.g., sulfonylurea + metfor

min + TZD

or

Add p.m. insulin to two-drug

regimen

NPH or glargine at HS

70/30 or Humalog Mix 75/25

before dinner

Step 5

Insulin twice daily

May sdd metformin or TZD if

insulin dose is over 1 U/

kg/d with suboptimal con

trol

Step 6

Basal-bolus insulin regimen

e.g., glargine at HS with lis

pro or aspart before each

meal

decreased similarly. However, as control improves with the addition of insulin, one should attempt discontinuing at least one agent.

As an alternative to bedtime N or glargine, premixed insulin (70/30 or Humalog Mix 75/25) can be implemented before dinner if the patient is >150% ideal body weight (22). Humalog Mix contains rapid-acting lispro, which may provide added convenience because it can be given just before eating rather than 30 minutes prior, and specifically targets postprandial glucose reduction. How-

a an

Table 3 Insulin Action Profiles

Insulin type

Onset

Peak

Duration

Lispro/aspart

5 min

1 hr

2-4 hr

Human Regular

30-60 min

2-3 hr

3-6 hr

Human NPH

2-4 hr

4-10 hr

10-16 hr

Human Lente

3-4 hr

4-12 hr

12-18 hr

Human Ultralente

6-10 hr

12-16 hr

18-20 hr

Insulin glargine

1-2 hr

? flat

About 24 hr

ever, the cost is significantly greater than that of standard 70/30 human insulin. When glargine at bedtime is the first insulin used, as may be preferable for many patients, a premixed insulin can later be substituted or a second injection of lispro or aspart can be given before dinner if isolated hyperglycemia is noted after dinner.

When evening insulin strategy fails, one can easily transition to twice-daily insulin with premixed insulin or self-mixed NPH/Regular or NPH/rapid-acting insulin analog before breakfast and dinner. Table 3 shows the time-action relationships of the various insulin products (22). Exact insulin requirements are difficult to predict due to intraindividual variability in insulin sensitivity. Because the change has usually been motivated by poor glucose control, the initial b.i.d. dose can safely be determined by first calculating the total daily insulin dose as 1.5 times the previous evening insulin dose. This 24-hour dose is then delivered in two evenly divided doses before breakfast and dinner.

When twice-daily dosing is ineffective, is associated with nocturnal hypoglycemia, or is too inflexible for a patient's needs, he or she progresses to a basal-prandial insulin regimen. That transition is easiest if the patient was initially on glargine as part of a combined evening insulin-oral agent regimen and simply adds pre-meal insulin while stopping any insulin secretagogue. The initial pre-meal insulin doses can be estimated from the total glargine dose—a similar daily mealtime insulin requirement is divided into three doses according to the relative size of the three meals. Alternatively, advanced instruction in carbohydrate counting can be used to better determine individual meal requirements by establishing a ratio of rapid-acting insulin analog to grams of carbohydrate consumed. This practice also offers added flexibility in lifestyle. The basal-prandial insulin approach can more safely facilitate calorie restriction for weight loss as well.

Another alternative to this dual insulin regimen is the use of rapid-acting insulin analog to cover prandial excursions while an oral agent covers basal requirements (Table 4). In one study, this regimen, aimed at postprandial glucose control, reduced HbA,c more than metformin-glyburide and BIDS regimens.

Table 4 Typical Protocol for Adding Insulin to Oral Agent Therapy

Continue oral agents, but reduce the sulfonylurea to 50% maximum dose if using NPH at bedtime or premixed insulin at dinner or to 25% if using glargine at bedtime

Begin with a single dose of 10 units in the evening (or may go to 0.15 U/ kg) in the evening: NPH at bedtime Glargine at bedtime 70/30 30 minutes before dinner

Humalog Mix 75/25 not more than 10 minutes before dinner

Measure the morning (fasting) blood glucose daily

Increase the insulin weekly by: 2 units if FBG is >120 4 units if FBG is >160

The goal is to have the morning glucose 90-130 mg/dl > 50% of the time if possible, with no symptomatic hypoglycemia

However, the study had some limitations, including poor success with the BIDS regimen aimed at reducing fasting blood glucose (23).

Any insulin regimen can benefit from the addition of insulin sensitizers when total insulin doses are high, i.e., 1 U/kg/day. Again, metformin is the preferred initial oral agent addition in this setting because it has a weight-reduction benefit. However, TZDs are very effective additions in patients who are highly insulin-resistant. As mentioned above, the prevalence of lower-extremity edema is higher when TZDs are used with insulin. However, many patients do not experience edema and weight gain, and fear of these complications should not preclude the use of these potentially highly effective agents if the patient is properly educated about possible problems. Both TZDs and metformin can be used with insulin simultaneously, but there is no reported experience with this practice. The cost would be significant if insulin doses are not significantly reduced by this approach.

SUMMARY

Type 2 diabetes will become an ever-increasing part of most medical practices in the United States. Individuals are developing diabetes at an earlier age and will experience longer durations of disease with associated progressive insulin deficits. Insulin therapy will therefore become a common requirement in managing type 2 diabetes. New insulin products and regimens are changing the

therapeutic approach. The combination of insulin with oral agents will remain an important first step in this form of diabetes, but many patients will progress to basal-prandial insulin regimens similar to those used in type 1 diabetes in recent years. The goal of therapy is to reach target HbAk levels of ^7.0% without exposing the patient to adverse effects.

REFERENCES

1. Mokdad AH, Ford ES, Cowman BA, et al. Diabetes trends in the US: 1990-1998. Diabetes Care 23:1278-1283, 2000.

2. American Diabetes Association. Economic consequences of diabetes mellitus in the U.S. in 1997. Diabetes Care 21: 296-309, 1998.

3. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulpho-nylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-853, 1998.

4. Stratton IM, Adler AI, Neil HAW, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. Br Med J 321:405-412, 2000.

5. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 24(suppl 1):S33-S43, 2001.

6. DeFronzo RA Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281-303, 1999.

7. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 281:2005-2012, 1999.

8. Pozzilli P, DiMario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 24:146-167, 2001.

9. lsomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683, 2001.

10. Malmberg K for the DIGAMJ Study Group. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. Br Med J 314:1512-1515, 1997.

11. Rivellese AA, Patti L, Romano G, et al. Effect of insulin and sulfonylurea therapy, at the same of level of blood glucose control, on low density lipoprotein subfractions in type 2 diabetic patients. J Clin Endo Metab 85:4188-4192, 2000.

12. Tudkin JS, Panahloo A, Stehouwer C, et al. The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in Type II diabetic subjects. Diabetologia 43:1099-1106, 2000.

13. Miller CD, Phillips LS, Ziemer DC, et al. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 161:1653-1659, 2001.

14. Rosenstock J, Schwartz SL, Clark CM, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 24:631-636, 2001.

15. Yki-Jarvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care 24:758-767, 2001.

16. Henry RR, Wallace P, Gumbiner B, et al. Intensive conventional insulin therapy for type II diabetes: metabolic effects during a 6-month outpatient trial. Diabetes Care 16:21-31, 1993.

17. Abrajra C, Colwell, JA, Nuttall FQ, et a). Veterans affairs cooperative study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial. Diabetes Care 18:1113-1123, 1995.

18. Rossetti L, Giaccari A, DeFronza RA. Glucose toxicity. Diabetes Care 13:610-616, 1990.

19. Yki-Jarvinen H, Kauppila M, Kujansuu E, et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 327:1426-33, 1992.

20. Yki-Jarvinen H, Ryysy L, Nikkila K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 130:389-396.

21. Riddle MC, Hart J, Bingham R, et al. Combined therapy for obese type 2 diabetes: suppertime mixed insulin with daytime sulfonylurea. Am J Med Sci 303:151-156, 1992.

22. Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 358:739-746, 2001.

23. Baslyr EJ. Stuart CA, Brodows RG, el al. Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbAlc. Diabetes Care 23:1236-1241, 2000.

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