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DOI: 10.1177/0145721705285642 © 2006 American Association of Diabetes Educators; Published by SAGE Publications
Treating the Spectrum of Type 2 DiabetesEmphasis on Insulin Pump TherapyFrom the University of Rochester, School of Medicine and Dentistry, Rochester, New York. Correspondence to Steven D. Wittlin, MD, Endocrine Practice Group, Strong Memorial Hospital, 601 Elmwood Avenue, Rochester, NY 14642.
Type 2 diabetes represents a spectrum of metabolic abnormalities with both insulin resistance and insulin deficiency (Table 1). Patients can present in a variety of ways. The "classic" patient with type 2 diabetes is obese, insulin resistant, and not prone to diabetic ketoacidosis (DKA). Atypical diabetes, also known as "Flatbush" diabetes, was first reported by the Downstate Medical Center in the Flatbush area of Brooklyn, New York. These patients are primarily African American and have typical features of type 2 diabetes interspersed with episodes of DKA, which may require intensive diabetes management. This is in contrast to patients with classic type 2 diabetes who generally do not experience DKA. Latent autoimmune diabetes of adults (LADA) is a type of diabetes that is diagnosed typically in nonobese adults and is characterized by antiglutamate acid decarboxylase or anti-islet cell antibodies. A total of 10% to 20% of patients with type 2 diabetes have these antibodies, which suggests that LADA is at least as prevalent in the general population as is type 1 diabetes. LADA has sometimes been referred to as "type 1  " diabetes. This term is a more
general term referring to thinner, insulin-requiring patients with type 2
diabetes and has also been called "burnt-out type 2."
Type 2 diabetes is characterized by a continuous decline in ß cell function in the presence of insulin resistance. A decline in ß cell function occurs throughout the development of glucose intolerance and goes from normal glucose tolerance to impaired glucose tolerance and then to overt diabetes mellitus.1 When patients present with type 2 diabetes, they have both insulin resistance and ß cell dysfunction. On average, patients have lost 50% of their ß cell function at the time they are diagnosed with type 2 diabetes (Figure 1).2 While ß cell dysfunction progresses over time, insulin resistance essentially plateaus. It is, therefore, the progressive decline in ß cell function that explains why patients with type 2 diabetes eventually require additional therapy to maintain glycemic control. Overall, by 6 years after entry into the UK Prospective Diabetes Study (UKPDS),2 almost 50% of patients with type 2 diabetes required the addition of insulin to their treatment regimens. When comparing patients with and without LADA, 94% of those with LADA required insulin at 6 years versus 14% of those patients who did not have LADA. As can be seen in Figure 2, glycosylated hemoglobin (A1C) levels increased over time among patients in the UKPDS, regardless of whether patients received conventional therapy or intensive therapy. However, in the Diabetes Control and Complications Trial (DCCT), intensive insulin therapy in patients with type 1 diabetes seemed to preserve ß cell function, as demonstrated by a lesser decline in C-peptide values over time (Figure 3).3
When glycemic control can no longer be achieved with 1 or 2 oral antidiabetic agents, insulin should be added. The addition of insulin therapy when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control. Intensive insulin therapy benefits ß cells, as shown in Figure 3.3 In an effort to bring A1C levels to goal, treatment of both fasting and postprandial glycemic excursions has taken on heightened importance in the care of patients with type 2 diabetes.5,6 As patients get closer to A1C goals, the need to successfully manage postprandial glucose levels significantly increases (Figure 4).7
While insulin is indicated in many patients with type 2 diabetes, its use is often delayed. This may be related to barriers and concerns expressed by either patients or health care providers (see the article in this issue by Meece8). Reluctance to initiate insulin therapy ranges from fear of weight gain and needle use to concerns about hypoglycemic events, cardiovascular complications, and cost. However, many reasons for this reluctance have been invalidated by new clinical evidence and better technologies. Today, insulin injections are generally not painful because of the availability of finer needles and insulin pens. With regard to weight gain, results of the DCCT9 showed that insulin-induced weight gain in patients with type 1 diabetes appeared to be associated with a family history of type 2 diabetes. In addition, hypoglycemic events are much less common in patients with type 2 diabetes who are treated with insulin (about one tenth of the incidence) when compared with type 1 diabetes.10 Although insulin resistance has been associated with cardiovascular disease in a few studies,11-13 there have been many studies that have shown no increase in cardiovascular disease (CVD) or a substantial decrease in CVD in patients treated with exogenous insulin.2,9,14,15 Furthermore, insulin is less expensive than most oral agents.16,17 All of this evidence suggests that the major barrier to insulin initiation is provider reluctance. It is important to note that exenatide (ByettaTM), the first glucagon-like peptide (GLP)–1 analog, was recently approved as an injectable therapy for patients with type 2 diabetes. The place of GLP-1 analogs in the management of type 2 diabetes is currently being evaluated.
Why Insulin Pump Therapy in Type 2 Diabetes?
Insulin administered by an insulin pump provides better day-to-day reproducibility, more reliable insulin availability, and less unexpected fluctuations in glycemic control (Figures 5 and 6).19,20 Small subcutaneous depots enhance the reproducibility of insulin delivery, which helps reduce the risk of exercise-induced hypoglycemia commonly seen with conventional subcutaneous insulin injections.
Because CSII provides basal insulin therapy with the ability to use bolus insulin (rapid-acting insulin) whenever needed, it is ideal for patients who eat often or erratically or for patients who want the flexibility to eat what and when they want without compromising glycemic control.
Raskin and colleagues21 evaluated a total of 132 CSII-naive patients with type 2 diabetes who were randomly assigned (1:1) to CSII (insulin aspart) or MDI therapy (bolus insulin aspart and basal NPH insulin) in a multi-center, open-label, randomized, parallel-group, 24-week study. A total of 93% of CSII-treated patients preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference (Figure 7).
In another trial, 40 obese, insulin-treated patients with type 2 diabetes were randomized to treatment with CSII or MDI therapy.22 At the end of the first 18-week treatment period, patients underwent a 12-week washout period during which they were treated with MDI plus metformin. They were then crossed over to the alternate treatment for an 18-week follow-up period. Results of the intention-to-treat analysis showed that CSII was superior to MDI in reducing A1C values. There was no significant change in weight or insulin dosage.
A 2-center, 12-month, prospective, randomized, controlled clinical trial compared the efficacy and safety of CSII with that of MDI in older adults (>60 years) with type 2 diabetes and marked obesity.23 In this population, patients treated with both CSII and MDI achieved excellent glycemic control with good safety and patient satisfaction. There was no statistically significant difference in hypoglycemic events or severe hypoglycemic events between treatment groups; however, there was a trend for less hypoglycemic events with CSII. It is not clear if this study of elderly patients can be extrapolated to most patients with type 2 diabetes. Moreover, it suggests that MDI should be attempted in elderly patients with marked obesity before considering insulin pump therapy.
There are several requirements that patients need to fulfill to be successful pump candidates. Patients must monitor their blood glucose at least 4 times daily, learn to carbohydrate count, have a "rescue algorithm" (eg, a correction factor), be sufficiently motivated, have an appropriate support system, and possess problem-solving skills. Table 2 summarizes insulin calculations that may be used to determine total daily doses for CSII in various patients with type 2 diabetes. When beginning insulin pump therapy in a lean, insulinopenic patient with type 2 diabetes, therapy is initiated in a fashion similar to that of patients with type 1 diabetes (eg, start with 0.3-0.8 U/kg/d). In type 2 patients with a normal build, slightly larger doses are used (eg, 0.5-1.0 U/kg/d). In obese patients, the starting dose should be 0.8 U/kg/d and can be increased vastly upward. Alternatively, patients with type 2 diabetes might choose to calculate the total daily dose as a percentage (typically 75%-100%) of the previous total daily dose used for MDI therapy. Approximately 50% of the total daily dose should be basal insulin. In lean patients, a 20% "dawn" adjustment is used. This means that during the first half of the night when the patient is sleeping, it is decreased by 20%, and during the second half of the night, it is increased by 20%. The remaining 50% of the total daily dose is for bolus insulin administration; it is used to cover carbohydrate intake and is based on an insulin-to-carbohydrate ratio.
In insulin pumps, the basal rate is the continuous flow of insulin used to regulate endogenous glucose production (in conventional insulin therapy, NPH, insulin glargine, or insulin detemir would be used for basal insulin). Mealtime boluses are used to prevent postmeal glucose excursions, which vary based on multiple factors, although they are based primarily on carbohydrates in the meal about to be ingested. Other factors include premeal blood glucose measurements, the patient's activity level, and any correction bolus dose needed for high blood glucose readings. Although not approved by the Food and Drug Administration for use in pumps, U-500 insulin can be an alternative in patients who require very large doses. This concentrated form of insulin has been shown by Knee and colleagues24 in a case series to be effective, to reduce the volume of insulin required, and to reduce the cost of both insulin and insulin supplies. The patient should also understand the basic principles of how insulin doses are calculated. For CSII to work, the basal doses, the correction doses, and the carbohydrate ratios must be determined. In addition, matching of insulin to carbohydrate intake is critical. The use of continuous glucose monitoring sensors can help determine insulin needs in patients using CSII. The most common source of bolus dose errors is miscalculation of carbohydrate intake. Another problem is overcorrection of postprandial elevations (correction bolus). "Insulin stacking" occurs when a correction dose of insulin is used to treat premeal or between-meal hyperglycemia when there is still significant active insulin in the patient's blood for which the patient does not account. Administering a full correction dose of insulin when there is significant active insulin will result in hypoglycemia. Other topics to review with patients include the correct use of self-monitored blood glucose results, appropriate dose calculations, and cautions to avoid "guesstimation." Accurate bolus insulin doses require calculations based on (1) current blood glucose levels, (2) target blood glucose levels, (3) carbohydrate-to-insulin ratios, (4) total grams of carbohydrate in meals, and (5) insulin sensitivity factors. Patients may often forego these calculations for insulin doses based on empirical estimates. A bolus calculator uses these parameters to generate a recommended bolus insulin dose. This has been shown to be effective in reducing the need for correction boluses and carbohydrate supplements.25
In the United Kingdom, patients who have had type 1 diabetes for 50 years or more receive a "medal" from Diabetes UK, formerly known as the British Diabetic Association. Bain and colleagues26 evaluated 400 medal holders (also known as the Golden Years Cohort) and found that the features of long-term diabetes in this cohort included normal body mass index (BMI) values (mean BMI = 25.0 kg/m2), low insulin doses (mean = 0.52 U/kg2), and a mean A1C level of 7.6%. In fact, many elderly patients with diabetes are lean and require insulin. Furthermore, DKA, hypoglycemia, or both may be problems in this population. Patients with these factors would benefit from the use of insulin pump therapy. Furthermore, an increasing number of elderly patients or their spouses are computer literate. Many elderly patients are extremely health focused and have the time to monitor and manage their diabetes and therefore may be pump candidates. Elderly patients who should be evaluated for pump use include those with an inability to achieve adequate glycemic control with MDI or those who have frequent hypoglycemia or nocturnal hypoglycemia with MDI. They may also be patients who desire greater lifestyle flexibility. They should be properly motivated, have appropriate problem-solving skills and support systems, and have a reasonable life expectancy. Estimating insulin dose by weight (70%-80% of MDI total daily dose) in elderly adults is similar to nonelderly adults; however, target blood glucose levels should initially be higher until the right regimen has been determined to avoid hypoglycemic episodes. Saline use is frequently helpful in patients who are somewhat "technologically challenged" in the training stages.
An added impetus for the use of pump therapy in the elderly comes from Medicare's decision to cover this method of treatment as long as certain criteria are satisfied. A recent amendment relaxed the C-peptide requirement (see below) and included coverage for patients with diabetes who have positive ß cell antibodies. Clinicians should be aware of the revised Medicare Insulin Pump Coverage Criteria that were issued in February 2005.27 Older patients must meet either criterion A or B and Medicare's definition of diabetes (positive ß cell antibody or the new C-peptide criteria). Criterion A. A new pump patient must complete a diabetes education program, require at least 3 injections of insulin per day, and make frequent self-adjustments of insulin for 6 months prior to starting CSII therapy. They must have documentation of their need to self-monitor blood glucose levels at least 4 times a day for 2 months prior to CSII therapy and meet 1 or more of the following criteria while on MDI therapy: A1C levels >7.0%, history of recurring hypoglycemic episodes, wide fluctuations of blood glucose levels prior to meals, experience the "dawn" phenomenon (fasting blood sugar levels >200 mg/dL [11 mmol/L]), or a history of severe glycemic excursions. Criterion B. A patient using pump therapy prior to Medicare enrollment must have documented his or her need to self-monitor glucose levels at least 4 times per day during the month prior to Medicare enrollment. The new criteria involve a positive ß-cell antibody test. To demonstrate this, obtain a copy of the patient's lab report including the laboratory reference range for ß cell antibodies and the patient's results if the results are out of this range. If these criteria are met, the patient meets the Medicare criteria. For patients with renal insufficiency and impaired creatinine clearance (actual or calculated from age, gender, weight, and serum creatinine clearance <50 mL/min), the revised C-peptide criteria require that the C-peptide levels be <200% of the laboratory's lower limit of normal. Levels need to be documented only once in medical records. For other patients, the C-peptide criterion remains <110% of the laboratory's lower limit of normal. The C-peptide is valid only when concurrent fasting blood glucose level is <225 mg/mL (12.4 mmol/L).
This case involves a 67-year-old retired female teacher who had a 3-year history of type 2 diabetes and a history of treatment of hepatitis C infection. Her A1C level upon presentation was 10.8%, despite 30 U of insulin glargine and an insulin lispro algorithm for meal-time coverage. Her blood glucose profile was characterized by the development of sporadic hyperglycemia and hypoglycemia. In addition, she had a history of diabetic nephropathy but no other complications. Her insulin correction factor was 1 U per 25 mg/dL. In the clinic, she was given a carbohydrate ratio of 1:10 and rapid-acting insulin lispro by pen. Despite this, her best A1C level was 8.0% with persistent hyperglycemia and hypoglycemia. One year ago, she was placed on CSII when she was very lean and weighed 123 pounds (56 kg). Therefore, her initial total daily insulin dose was approximately 0.7 U/kg (39 U). Her basal rate was determined to be 0.5 U/h at midnight, 1.0 U/h at 4 AM, and 0.8 U/h at 9 AM. Her bolus dose was 1 U/10 g of carbohydrate with a correction factor of 1 U for every 75 mg/dL over target. Her most recent A1C level was 6.5%, and she is experiencing less hypoglycemia, so much so that she no longer fears going shopping alone.
CSII therapy is emerging as a treatment option for the entire spectrum of diabetes, from adults and children with type 1 diabetes (see the Owen and Fisher articles in this issue) to the elderly and patients with type 2 diabetes. Technological advances and the use of improved technologies by motivated patients are also prompting the increased use of CSII therapy. There are many potential metabolic advantages of CSII therapy in patients with type 2 diabetes, including improved glycemic control and more reliable pharmacokinetic delivery of insulin, which results in less hypoglycemic episodes and a lower insulin requirement, as well as improved quality of life. CSII therapy is an excellent alternative for patients with type 2 diabetes who require insulin if patients are properly selected and adequate doses of insulin are prescribed. One can look forward to further research to validate these concepts.
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