Practical Concepts for Initiating Insulin Therapy: Type 2 Diabetes

Introduction

Diabetes is the fifth leading cause of death in the United States.¹ Studies have shown that patients can achieve some measure of glycemic control when clinicians recommend intensive therapies, provide referrals to diabetes educators for diabetes self–management training (DSMT), and offer recommendations for prevention or delay of disease progression through lifestyle changes or modifications.²

Oral Antidiabetes Drugs: A Brief Overview

A number of oral antidiabetes drugs (OADs) are available. Each drug class has a different mechanism of action and provides some measure of physiologic glycemic control (Table 1).

Table 1. Oral Antidiabetes Drug Classes*

Class	Drugs	Starting Dose*
Sulfonylureas	Glipizide Glyburide Glimepiride	5 mg/morning 2.5–5 mg/morning 5 mg/morning
Meglitinides	Nateglinide Repaglinide	120 mg tid preprandially 0.5 mg preprandially
Biguanide	Metformin	1000 mg once daily with the evening meal
Thiazolidinediones	Pioglitazone Rosiglitazone	15–30 mg/d 4 mg administered either as a single dose once daily or in divided doses twice daily

*There is no fixed dosage regimen for any hypoglycemic agent. Please refer to prescribing information of individual drugs for specific dosing information and available data regarding anticipated decrease in A1C.

Progression of Disease: ß-Cell Dysfunction

Two of the characteristics of type 2 diabetes are a progressive decline in ß-cell function and chronic insulin resistance.³ Debate continues as to whether impaired insulin secretion is a result of reduced ß-cell mass, a defect in the secretory mechanism of ß-cells, or both.⁴ It is believed, however, that by the time patients are diagnosed with type 2 diabetes, they may already have lost as much as 50% of ß-cell mass.⁴ A genetic predisposition, combined with a high-caloric diet and sedentary lifestyle, may lead to early hyperglycemia that affects early-stage ß-cell mass or function.⁴ This supports the finding that diabetes is a progressive disease that requires intensive treatment.

Initiating Insulin Therapy

Exogenous insulin is the most physiologic, most rapid, and most effective pharmacologic treatment available for enabling patients to reach normoglycemia.⁵ As is the case with some of the OADs, the main disadvantage is the potential to cause hypoglycemia. Physicians have cited a number of other reasons for unwillingness to start insulin therapy at an earlier stage in the course of disease management. These include (1) feeling that starting insulin would mean their treatment recommendations were not followed; (2) lack of understanding that using insulin would help to manage diabetes better; (3) misunderstanding of cost; and (4) provider’s lack of urgency to start insulin until absolutely essential.²

The Treat-to-Target Trial⁶ suggests that insulin be considered in overweight patients whose A1C levels are between 7.5% and 10% despite therapy with OADs.

Physicians have cited numerous difficulties in treating patients with type 2 diabetes,^2,5 including the following factors:

• Treatment includes complex interventions and ongoing support to help patients modify lifestyle behaviors (eg, diet and exercise)
• Patients have to actively manage the disease through diet, exercise, self-monitoring of blood glucose (SMBG), and pharmacotherapy
• Physicians and practice staff optimally must coordinate interventions with multidisciplinary teams
• Physicians have to support patients through disease progression, alleviate fears, and provide encouragement when insulin therapy is required
• Patients need to understand that progression to injections of insulin does not mean they have failed self-management

A number of concerns that are common to patients include the following⁷:

• Fear of needles or pain from injections
• Fear of hypoglycemia
• Weight gain
• Adverse impact on lifestyle
• Perception that the need for insulin means the disease is more severe and dangerous
• Belief that insulin causes complications
• Fear of being treated differently by family and friends

The following treatment philosophy may assist physicians and patients: at the time of diagnosis, explain how the disease progresses, including the observation that insulin therapy will likely be needed. Patients may then anticipate and accept more openly the need to self-inject insulin when the time comes. “Diabetes gets harder to handle as the years go by. The longer you live with it, the more likely it is that you will need powerful medications like insulin to control it. And because you are relatively healthy, you’re probably going to live a long time. So it is fairly likely that you’ll need insulin at some point.”²

A number of resources are available that provide referrals to diabetes education programs, patient education materials, and tips for self-management support for the patient who is started on insulin therapy. Resources include the American Diabetes Association (www.diabetes.com) and the American Association of Diabetes Educators (www.aadenet.org).

Available Insulin Therapies

The primary goal of insulin therapy is to reach and sustain near-normal glycemic levels in order to prevent acute metabolic complications, and to prevent or delay the onset of long-term complications such as cardiovascular disease, neuropathy, nephropathy, retinopathy, and lower-extremity circulatory conditions. Historically, initiating insulin treatment has been delayed until later-stage disease; however, studies show that earlier initiation confers an advantage.⁵ As diabetes progresses, a combination of insulin products taken 2 or more times daily provides optimal therapy for meeting both basal insulin needs and prandial glycemic control.⁵ In early-stage diabetes, the administration of a single injection of a longer-acting basal insulin may effectively control BG during the night and optimize fasting glucose levels.⁵ When insulin is initiated earlier in the disease state than has historically been the case, this therapy has the potential to preserve ß-cell function and delay disease progression⁵ (Table 2).

Table 2. Insulins Currently Available in the United States*

Type of Insulin	Onset of Action (min/h)	Time to Peak Action (h)	Duration of Action (h)
Aspart	10–20 min	1–3	3–5
Lispro	10–15 min	0.8–4.3	3–5
Regular	30 min	2.5–5	8
NPH	1.5 h	4–12	24
Glargine	1–1.5 h	Peakless	24

*Please refer to prescribing information of individual drugs.

Dosing

All insulin formulations exhibit individual variability of action between patients and even in the same patient at different times and under different circumstances.

The Council for the Advancement of Diabetes Research and Education (CADRE) recommends that insulin therapy be considered if a patient’s A1C level is >7% regardless of lifestyle modifications or OAD therapy.⁵ The Treat-to-Target Trial⁶ specifically recommends that a practical approach is to start therapy with 1 evening basal injection of ~10 units of glargine or NPH insulin. Dosing can be titrated weekly as needed. The dose titration algorithm that is suggested is as follows: if the fasting blood glucose (FBG) is between 100 mg/dL and 120 mg/dL based on the patient’s SMBG diary, the evening insulin dose can be increased by 2 units, adding 1 unit for each additional FBG increment of 20 mg/dL.⁷ Another approach would be to initiate insulin preprandially while continuing OADs⁸ or to add a second injection of NPH in the morning, although the latter would not address correction of pronounced nocturnal hypoglycemia.⁵

Insulin Delivery Systems

Insulin pens are the predominant insulin delivery system in most of the world, but syringes and insulin vials still dominate in the United States. Pens are made by Novo Nordisk, Eli Lilly, Disetronics, and Owen Mumford.

Some pens use replaceable insulin cartridges, while other pens are disposable after the cartridge is finished. All pens use replaceable needles, and most use special needles that are extremely short and of fine gauge.

Unlike syringes, pens need to be held in place for several seconds after the insulin has been delivered to ensure that no insulin leaks from the site. Syringe users who switch to pens should pay close attention to the injection site and test their blood glucose more frequently as they become accustomed to pen injectors. For more information about insulin delivery devices, see the Slide Library section of this Web site.

Insulin pump therapy is an alternative to multiple daily injections, although it is somewhat controversial in patients with type 2 diabetes.⁹ The debate centers on the need for a high degree of medical supervision and patient self-management education and training when beginning pump therapy.⁹ Insulin pumps have an advantage over insulin injections in that they allow flexibility in the timing of meals and the programming of changes in the basal insulin delivery rate to meet anticipated or unanticipated increase or decrease in insulin need. They also allow for flexibility in meals and activity. These features can be advantageous in controlling the normal dawn rise in blood glucose concentration before breakfast, preventing anticipated hypoglycemia from exercise or fasting, and treating stress or illness-related hyperglycemia.⁹

Conclusion

Type 2 diabetes is a progressive disease that invariably leads to severe ß-cell dysfunction. Most patients will need insulin therapy at some point in their disease progression. Recent studies indicate that the initiation of insulin therapy should not be delayed.

References

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2. Polonsky WH, Jackson RA. What’s so tough about taking insulin? Addressing the problem of psychological insulin resistance in type 2 diabetes. Clin Diabetes. 2004;22:147-150.


3. Butler AE, Janson J, Bronner-Weir S, Ritzel R, Rizza RA, Butler PC. ß-cell deficit and increased ß-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-110.


4. Donath MY, Halban PA. Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia. 2004;47:581-589.


5. Rosenstock J, Riddle MC. Insulin therapy in type 2 diabetes. In: Cefalu WT, Gerich JE, LeRoith D, eds. The CADRE Handbook of Diabetes Management. New York, NY: Medical Information Press; 2004.


6. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086.


7. Funnell MM, Kruger DF, Spencer M. Self-management support for insulin therapy in type 2 diabetes. Diabetes Educ. 2004;30:274-280.


8. Kilo C, Mezitis N, Jain R, Mersey J, McGill J, Raskin P. Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin. J Diabetes Complications. 2003;17:307-313.


9. Schade DS, Valentine V. To pump or not to pump. Diabetes Care. 2002;25:2100-2102.