Rescue, augmentation, and replacement of beta-cell function

Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function

Jennifer A. Mayfield

Twenty-level of 7 seven percent of persons with type 2 diabetes use insulin therapy, but less than one half achieve the recommended A1C percent or less. (1) These statistics suggest that suboptimal insulin therapy is too common. New insulin preparations and a better understanding of insulin physiology provide more options for family physicians attempting to effectively tailor insulin therapy to the needs of individual patients.

This overview describes how basal and bolus insulin release in type 2 diabetes differs from normal patterns of insulin release and discusses the indications for insulin therapy and injectable insulin characteristics. The authors present evidence supporting various insulin regimens to restore, augment, or replace beta-cell function and offer suggestions for using analogue insulins.

Pathophysiology of the Beta Cell

Blood glucose is derived from carbohydrates absorbed in the gut and produced in the liver. Absolute and increasing blood glucose levels stimulate insulin release. (2) The postprandial glucose influx can be 20 to 30 times higher than hepatic production between meals. Phase 1 insulin release, lasting 10 minutes, sup-presses hepatic glucose production and facilitates phase 2 release, which lasts two hours and covers mealtime carbohydrates. Between meals, a low continuous insulin level, called basal insulin, serves ongoing metabolic needs.

The normal beta cell responds in a linear fashion to blood glucose levels. The slope of this response is steeper after fasting and flattened following prolonged exposure to high glucose levels. This loss of responsiveness to glucose levels, which may be reversible in the earlier stages, also is called beta-cell exhaustion or glucose toxicity. (3)

In type 2 diabetes, phase 1 release is absent, and phase 2 release is delayed and inadequate. The sharp spike of mealtime insulin release occurring in normal persons (white back-ground in Figure 1) is delayed, prolonged, and insufficient in amount in patients with type 2 diabetes. Before diagnosis and treatment, the beta cell produces excess insulin to accommodate insulin resistance, but eventually the beta cell is replaced with amyloid, and insulin production declines. (4)

[FIGURE 1 OMITTED]

When type 2 diabetes is clinically diagnosed, only 50 percent of normal beta-cell function remains. The United Kingdom Prospective Diabetes Study (UKPDS) (5) demonstrated that this function continues to deteriorate over time despite treatment with diet, exercise, metformin (Glucophage), sulfonyl-ureas, or insulin. Thiazolidinediones appear to preserve beta-cell function in women who had gestational diabetes, thus potentially pre-venting or delaying the onset of diabetes. (6) However, the ability of these drugs to preserve beta-cell function in patients with type 2 diabetes has not yet been proved.

Beta-cell function cannot be estimated accurately on the basis of endogenous insulin levels because of the pulsatile release pattern and short half-life (six to seven minutes). A more accurate estimate is provided by levels of C-peptide, a byproduct of insulin production with a half-life of 30 minutes. However, a low C-peptide level cannot differentiate nearly extinct beta-cell function from reversible glucose toxicity; thus, its determination rarely changes therapy.

Options

Endogenous insulin release can be stimulated by meglitinides (phase 1) or sulfonylureas (phase 2). Sulfonylureas have a 5 to 10 percent annual failure rate (fasting plasma glucose level greater than 200 mg per dL [11.1 mmol per L]). (7)

Injectable insulin is categorized as basal or bolus insulin based on the duration of action (Table 1 (8) and Figure 2). Basal insulins include neutral protamine Hagedorn (NPH) or isophane insulin (Novolin N, Humulin N), ultralente (extended insulin zinc suspension), and the insulin analogue glargine (Lantus). (9) Bolus or mealtime insulins include regular insulin (Novolin R, Humulin R) and the analogue forms aspart (NovoLog) and lispro (Humalog). (10) Premixed formulations incorporate NPH and regular or rapid-acting analogues. Inhaled, transdermal, and oral insulin formulations are in development.

[FIGURE 2 OMITTED]

Traditional insulins (i.e., regular, NPH, and ultralente) have two features that complicate therapy. First, their absorption profiles are erratic, creating day-to-day fluctuations in glycemic control. (9) Second, their delayed onset of action and peak activity requires coordination of injection and meals. Regular insulin must be injected 30 to 60 minutes before the meal to match postprandial glucose influx. NPH may cause hypoglycemia during its peak at four to 10 hours after injection unless the patient remembers to eat. Premixed formulations of NPH and regular insulin provide a bimodal pattern of insulin activity that rigidly dictates meal size and timing for the next 12 hours.

These problems are avoided with analogue insulins (i.e., glargine, aspart, and lispro)–so named because one to three amino acids have been substituted in the human insulin protein, producing altered absorption rates and more reliable absorption profiles. Lis-pro and aspart are active within 15 minutes and peak in about one hour, mimicking normal mealtime insulin release. (10) Glargine provides a peakless, continuous release over 24 hours that approximates a normal basal pattern. (9,11) The analogue insulins cost 60 to 100 percent more than traditional insulins.

Indications

Insulin therapy always can achieve glycemic control and may be initiated at any time.

An algorithm for instituting insulin therapy is provided in Figure 3. The most common indication for insulin therapy is failure to achieve glycemic control with diet, exercise, and oral medications. Within three years of diagnosis, only 33 percent of patients treated with metformin and sulfonylurea have an A1C level that is less than 7 percent. (12) In the UKPDS, (13) an A1C level of 7 percent or less was found to decrease the risk of microvascular outcomes–mainly retinal photocoagulation–but not cardiovascular disease. However, in the Steno-2 study, (14) a combination of glycemic, lipid, and blood pressure control reduced mortality by 50 percent compared with usual therapy. Insulin therapy also is indicated in patients with contraindications to antidiabetic medications. (15)

[FIGURE 3 OMITTED]

Intensive insulin therapy was found to reduce morbidity and mortality in critically ill patients in a surgical intensive care unit compared with usual therapy. (16) In patients who had experienced a myocardial infarct, intensive insulin therapy resulted in a 30 percent lower risk of death compared with usual therapy. (17) Pregnant women with poorly controlled type 2 diabetes should be given insulin to stabilize glucose levels. Tight glycemic control before conception decreases the risk of miscarriage and birth defects (18) and, in the third trimester, tight control decreases macrosomia and its attendant complications. (19)

Glucose toxicity, which is exhibited as a fasting plasma glucose level greater than 250 mg per dL (13.9 mmol per L), and ketonuria, weight loss, or symptomatic hyperglycemia, can be addressed promptly with insulin therapy. Many patients regain beta-cell function after a few weeks of intensive therapy, enabling them to return to management with diet or oral medication for several months to years. (20,21)

Contraindications and Adverse Effects

There are no medical contraindications to insulin therapy. Although no insulin has a category A pregnancy classification, regular and NPH insulin have been used extensively in pregnant women. Lispro has a category B classification, (22) and aspart and glargine have a category C classification. (23,24) Glargine is approved for use in patients six years and older (24) ; no other insulins have an age restriction.

The most serious adverse effect of insulin therapy is hypoglycemia, but the frequency and severity of this effect is less in type diabetes than in type 1 diabetes. In the UKPDS, (13) major hypoglycemia occurred in 2.3 percent of patients per year who were treated with insulin compared with rates of 0.1 to 0.4 percent in those on diet or sulfonylurea therapy. The risk of hypoglycemia increases significantly when the A1C level is below 7.4 percent. (25) Hypoglycemia risks can be minimized with use of analogue insulin; careful timing of injections, meals, and exercise; frequent self-monitoring of blood glucose levels; and patient education about self-adjustment of the insulin dose and management of hypoglycemia.

Weight gain is a common side effect of insulin therapy. In the UKPDS, (13) patients taking insulin gained 4 kg (8 lb, 13 oz) more than those treated with diet therapy over 10 years. Weight gain can be modified by increasing exercise, restricting calories, and administering metformin concurrently. (25,26) The benefits of insulin administration out-weigh the health risks of increased weight.

Exogenous insulin does not increase the risk of macrovascular disease or exacerbate insulin resistance. (13) All insulins are made using genetic recombinant techniques, so insulin allergy is uncommon.

Therapy Regimens

Theoretically, the ideal insulin therapy regimen should mimic normal physiologic insulin release (Figure 1). The insulin regimen should be tailored to the patient’s degree of hyperglycemia, the risks associated with hypoglycemia, comorbid conditions, the ability to adhere to a routine and understand and master the information and skills, and the cost. Table 2 offers tips on initiating insulin therapy.

Augmentation therapy is effective in patients with residual but insufficient beta-cell function, which is exhibited as failure to maintain the A1C goal while taking oral medications. (15) Augmentation therapy usually is provided with basal insulin using bedtime NPH (Figure 4), NPH twice daily, ultralente once daily, or glargine once daily, adjusted to maintain a fasting plasma glucose level between 90 and 130 mg per dL (5 and 7.2 mmol per L). Augmentation also can be provided at mealtime using regular insulin (Figure 5), aspart, or lispro (27,28) adjusted to maintain two-hour postprandial glucose levels of 180 mg per dL (10 mmol per L) or less. Compared with a single basal insulin injection, the same amount of insulin divided into several bolus injections provides fewer postprandial glucose fluctuations, a lower A1C level, and greater weight gain. (29)

[FIGURES 4 & 5 OMITTED]

Bolus insulin without basal insulin, called sliding-scale therapy, often is blamed for erratic glycemic control in hospital settings. In an observational study of hospitalized patients of unspecified diabetes type, those treated with sliding-scale therapy had a threefold higher risk of hyperglycemia. (30) Patients too sick to use their usual oral medications should receive basal insulin with periodic bolus adjustments that are called supplemental or corrective insulin.

Replacement therapy using basal-bolus insulin regimens is indicated for patients who need intensive control or have failed augmentation therapy. Short-term rescue therapy for glucose toxicity employs the same regimens. The most convenient basal-bolus regimen uses split-mixed injection of NPH and regular insulin before breakfast and dinner but requires rigid adherence to a set meal size and time. Premixed formulations may not match patient requirements. The morning NPH may not provide adequate coverage for lunch, and the evening NPH may cause nocturnal hypoglycemia. If NPH wanes in the early morning, resulting in an elevated fasting plasma glucose level, the second NPH insulin injection can be moved to bedtime, keeping the regular injection at dinner, for a total of three injections a day using two insulin vials (Figure 6).

[FIGURE 6 OMITTED]

Four injections a day of basal-bolus insulin provide a better approximation of nor-mal insulin release and more flexibility for patients with unpredictable schedules. Regimens include NPH and regular insulin, NPH with aspart or lispro, or glargine and aspart or lispro (Figure 7). In pregnant women and those planning pregnancy, traditional split-mixed, premixed, or basal plus meal-related insulin regimens are preferred.

[FIGURE 7 OMITTED]

In type 2 diabetes treated with mealtime lispro, A1C levels, quality of life, and number of hypoglycemic episodes are similar to those of regular insulin. (31-33) Lispro and aspart provide one- and two-hour postprandial glucose levels that are 30 and 50 percent lower than regular insulin, respectively. (28,31) This finding may be clinically important if postprandial control is demonstrated in a prospective study to provide as much cardiovascular benefit as has been noted in observational studies. (34)

In type 1 diabetes, when lispro is compared with regular insulin, it provides a better quality of life because of schedule flexibility, less hypoglycemia and hyperglycemia, and less weight gain, (31) suggesting that rapid-acting analogues may be useful in patients with severe insulin deficiency (C-peptide level [less than or equal to] 0.2 pmol per mL35), frequent severe hypoglycemia, or an unpredictable schedule.

Basal coverage with glargine provides A1C levels similar to those of NPH, but with less nocturnal hypoglycemia (4.0 versus 6.9 episodes per patient-year) and less frequent severe hypoglycemia (3.0 versus 5.1 episodes per patient-year).36-38 Glargine injected in the morning rather than at bed-time, titrated to a fasting plasma glucose goal of 100 mg per dL (5.6 mmol per L) or less, resulted in a lower A1C level (7.8 per-cent versus 8.1 percent) and less nocturnal hypoglycemia (17 percent versus 23 percent of patients with one or more episodes). (39)

The most faithful imitation of normal beta-cell function is provided by an implant-able insulin pump. A study of patients with type 2 diabetes demonstrated reduced weight gain, less frequent episodes of mild clinical hypoglycemia, and improved overall quality of life with the pump, compared with multiple daily injections. (40)

Dosing

The starting insulin dose for augmentation is calculated as 0.2 units per kg per day. (15,41) Another safe calculation is units of insulin per day equals fasting plasma glucose level in mmol per L. For example, a patient with a fasting plasma glucose level of 250 mg per dL (13.9 mmol per L) would be given 14 units of insulin each day. (41) The starting dose for replacement therapy is 0.5 mg per kg per day. Twofold to fourfold higher doses often are required for patients with insulin resistance. (15) There is no limit to the amount of insulin that can be used safely. U-500 (500 units per 1 mL) regular insulin is available for use in patients who require large amounts of insulin. Volumes greater than 0.5 mL (50 units of U-100 insulin) should be split and injected in separate areas to facilitate absorption.

Fifty to 60 percent of the total insulin dose should be provided as basal form and 40 to 50 percent as bolus form. Table 3 offers suggestions for initiating glargine therapy. (38,39)

The mealtime bolus is the sum of four factors that spell “SAFE.”

Supplemental Insulin. Supplemental (or correctional) insulin is added or subtracted to bring the pre-meal or bedtime glucose levels into the desired range. Insulin-sensitive patients require 1 unit of insulin to change the blood sugar level by 50 mg per dL (2.8 mmol per L); insulin-resistant patients experience a smaller change.

Activity. The dose should be decreased by 30 percent for postprandial exercise of less than one hour; by 40 percent for exercise of one to two hours; and by 50 percent for exercise of more than two hours. Increased insulin sensitivity may persist for 12 to 48 hours after exercise and can cause clinical hypoglycemia. (42,43) The insulin dose may decrease as patients train, improve physical fitness, reduce body fat, and decrease insulin resistance.

Food. Insulin to cover anticipated meal intake is based on the patient’s insulin-to-carbohydrate ratio. Insulin-sensitive patients require approximately 1 unit of insulin per 15 g of carbohydrate, but the ratio is often lower (1:10 or 1:5) in insulin-resistant patients. The insulin-to-carbohydrate ratio may vary by time of day or with certain foods (i.e., pizza). A nutritionist or certified diabetes educator can teach carbohydrate counting and suggest insulin adjustments to diet.

Experience. The self-monitoring record of blood glucose levels and insulin injections provides a way of learning what works for each patient. Blood glucose and insulin logs should be reviewed weekly until patients reach their goal. Adjustments should be made one at a time, changing a single injection dose 5 to 20 percent. The physician should address persistent hypoglycemia first, then increase basal insulin until the fasting plasma glucose level is 90 to 130 mg per dL, followed by adjustment of preprandial levels to 90 to 130 mg per dL. If the patient is still not at the A1C goal, the mealtime dose should be increased or the insulin should be switched to a rapid-acting analogue to reduce postprandial glucose levels to less than 180 mg per dL.

Oral Medications Plus Insulin

The synergistic effect of oral antidiabetic medications with insulin may allow the insulin dose to be reduced by up to 50 percent. (41) Metformin with insulin decreases weight gain, hypoglycemia, and diabetes-related end points. (26,44) Metformin does not need dose adjustments when administered with insulin. The combination of insulin with thiazolidinedione drugs (i.e., rosiglitazone [Avandia] and pioglitazone [Actos]) may cause edema and is contraindicated in patients with congestive heart failure. Pioglitazone is restricted to a 4-mg dose if co-administered with insulin. (45)

Co-administration of insulin with sulfonylureas may lower A1C levels and reduce the total daily insulin requirement if some beta-cell function remains. (41) Sulfonylureas are absorbed better if glucose levels have been normalized with insulin. (46)

Patients randomized to insulin NPH/regular 70/30 plus metformin achieved similar A1C levels, fasting plasma glucose levels, and weight gain but had lower daily costs ($3.20 versus $10.40) and treatment failures (16 percent versus 3.5 percent) than patients randomized to triple oral medication (a sulfonylurea, metformin, and thiazolidinedione). (47)

The online version of this article, available at http://www.aafp.org/afp/20040801/489.html addresses three illustrative cases.

The authors thank Evangeline Erskine, M.D., for comments on the manuscript. Dr. Mayfield indicates that she does not have any conflicts of interest. Sources of funding: none reported. Dr. White receives honoraria and/or consulting fees from AstraZeneca, Aventis Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Medtronic MiniMed, Pfizer Inc., and Takeda Pharmaceuticals America, Inc.

TABLE 1

Description of Onset, Peak, and Duration of Insulins

Peak

Insulin Onset (hours)

Bolus or mealtime insulin

Aspart (NovoLog) 5 to 10 minutes 1 to 3

Lispro (Humalog) < 15 minutes 0.5 to 1.5

Regular (Humulin R, 30 to 60 minutes 2 to 3

Novolin R)

Basal insulin

NPH (Humulin N, Novolin N) 2 to 4 hours 4 to 10

Lente (insulin zinc 3 to 4 hours 4 to 12

suspension)

Ultralente (extended 6 to 10 hours Peakless

insulin zinc suspension)

Glargine (Lantus) 1 hour, 6 minutes Peakless

Combinations

50% NPH/50% regular 30 to 60 minutes Dual

70% NPH/30% regular 30 to 60 minutes Dual

(Humulin R 70/30,

Novolin R 70/30)

75% NPL/25% lispro < 15 minutes Dual

(Humalog 75/25)

70% NPH/30% aspart 5 to 10 minutes Dual

(NovoLog 70/30)

Usual Usual

effective maximum

duration duration

Insulin (hours) (hours) Cost *

Bolus or mealtime insulin

Aspart (NovoLog) 3 to 5 4 to 6 59

Lispro (Humalog) 2 to 4 4 to 6 59

Regular (Humulin R, 3 to 6 6 to 10 28

Novolin R)

Basal insulin

NPH (Humulin N, Novolin N) 10 to 16 14 to 18 28

Lente (insulin zinc 12 to 18 16 to 20

suspension)

Ultralente (extended 18 to 20 20 to 24 28

insulin zinc suspension)

Glargine (Lantus) 24 24 51

Combinations

50% NPH/50% regular 10 to 16 14 to 18

70% NPH/30% regular 10 to 16 14 to 18 28

(Humulin R 70/30,

Novolin R 70/30)

75% NPL/25% lispro 10 to 16 14 to 18 59 ([dagger])

(Humalog 75/25)

70% NPH/30% aspart 10 to 16 14 to 18 59

(NovoLog 70/30)

NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro.

*–Estimated cost to the pharmacist for one 10-ml vial based on

average wholesale prices in Red book. Montvale, N.J.: Medical

Economics Data, 2004. Cost to the patient will be higher, depending

on prescription filling fee.

([dagger])–20-mL volume only–cost shown is one half of the cost

of a 20-mL vial.

Adapted with permission from Resource guide 2004. Insulin. Diabetes

Forecast 2004;57:RG16.

TABLE 2 Tips for Initiating Insulin Therapy

Discuss the possibility of insulin therapy well in advance of when it

needs to be implemented, so patients have time to explore their fears

and obtain information. Do not use insulin therapy as a threat when

discussing compliance with diet, exercise, and medications–even

compliant patients eventually require insulin.

Stock several insulin-start packets with instruction sheets,

informational handouts, syringes, needles, and insulin samples to

facilitate insulin initiation.

Consider use of insulin pens and other devices that do not require

syringes.

Team up with a certified diabetes educator to teach patients

nutritional therapy and how to adjust their insulin. Communicate the

goals that you and the patient have discussed. Train one of the nursing

staff to teach insulin administration to patients who need to start

immediately and cannot wait for a scheduled meeting with the educator.

Tailor the insulin type and regimen to fit the patient’s lifestyle and

budget. Patients who have irregular hours and meals may find that

insulin glargine and rapid-acting analogues provide more flexibility,

while those with a set routine can do well with the traditional

insulins.

Schedule patients for follow-up within one week to adjust insulin doses

and provide more education. Maintain contact with the patient through

office visits, telephone calls, fax, or secure e-mail every three to

seven days until blood sugar level is at the goal.

Always ask for the self-monitoring blood glucose log. Train staff to

remind the patient, when making an appointment, to bring the log. Have

the patient describe how he or she would make dose change decisions.

Reinforce good decisions and gently correct poor decisions. Use the

accompanying patient information handout to clarify future doses and

adjustments.

Always find something to praise.

Useful resources from the American Diabetes Association include

Practical

Insulin: A Handbook for Prescribers, 2002 (http://store.diabetes.org)

and the Diabetes Forecast Resource Guide published every January

(http://www.diabetes.org/diabetes-forecast/resource-guide.jsp).

TABLE 3

Starting Glargine (Lantus) Therapy in Patients with Type 2 Diabetes

Initial dose

Patient has not taken insulin previously:10 units or 0.15 units per kg

once daily *

Patient has taken NPH insulin previously: Use 80 percent of the total

daily dose of NPH insulin. ([dagger]) Timing of injection: inject at

the same time every day.

Monitor FPG.

If FPG <80 mg per dL (4.4 mmol per L) on three consecutive days or

[greater than or equal to] 3 times in a week, decrease glargine

insulin by 2 units.

Review the FPG once a week. Increase insulin dose based on the FPG

levels of the past two days. Do not increase the dose more often than

once a week.

Mean of self-monitored FPG

from preceding two days, Increase insulin dose

mg per dL (mmol per L) (units)

>180 (10) 8

140 (7.7) to 180 6

120 (6.7) to 140 4

100 (5.6) to 120 2

The effects of glargine last 16 to 24 hours. Some patients require a

twice-daily schedule to maintain basal levels.

NPH = neutral protamine Hagedorn; FPG = fasting plasma glucose.

*–This starting dose is conser vative to minimize the risk of

hypoglycemia in a patient who may be insulin-sensitive.

([dagger])–Approximately 80 percent of NPH activity functions as

basal insulin; the other 20 percent functions as bolus insulin during

its small activity peak.

Adapted with permission from Riddle MC, Rosenstock J, Gerich J.

The treat-to-target trial: randomized addition of glargine or human

NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care

2003;26:3081.

Strength of Recommendations

Key Recommendation Label References

Rescue therapy using intensive C New-diagnosis diabetes (3, 20)

insulin therapy should be used Longstanding diabetes (21)

for patients with glucose

toxicity (i.e., fasting plasma

glucose >250 mg per dL (13.9

mmol per L), ketosis, weight

loss).

Augmentation with basal or C Basal insulin (15)

bolus insulin therapy can Bolus insulin (27)

restore glycemic control in

patients with residual

beta-cell function.

Replacement therapy with A 17

intensive insulin therapy

should be used for patients

with acute myocardial

infarction.

Replacement therapy with B 16

intensive insulin therapy

should be used for patients

in the surgical intensive care

unit.

Replacement therapy with B 18, 19

intensive insulin therapy

should be used for women with

diabetes who are pregnant or

planning a pregnancy.

Basal therapy with glargine A 36, 37, 38

(Lantus) provides better A1C

and less nocturnal

hypoglycemia when compared

with bedtime NPH (Novolin N,

Humulin N).

Bolus therapy with A 31, 32, 35

short-acting analogue (lispro

[Humalog]) provides no

advantage over regular insulin

(Humulin R) for patients with

type 2 diabetes, but improves

treatment satisfaction and

lessens hypoglycemia for

patients with type 1 diabetes.

Hospitalized patients unable B 30

to take their usual medication

should receive basal insulin

with periodic bolus

adjustments.

Metformin (Glucophage) A 25, 26

combined with insulin is

preferred to insulin-only

therapy.

Insulin plus metformin is cost C 47

effective compared with triple

oral medication therapy.

Key Recommendation Comments

Rescue therapy using intensive Several small uncontrolled trials of

insulin therapy should be used patients with new-diagnosis or

for patients with glucose longstanding diabetes demonstrate

toxicity (i.e., fasting plasma that intensive insulin therapy of

glucose >250 mg per dL (13.9 short duration may restore beta-cell

mmol per L), ketosis, weight function for many months to years.

loss).

Augmentation with basal or A randomized controlled trial

bolus insulin therapy can demonstrated lower fasting plasma

restore glycemic control in glucose levels with basal insulin as

patients with residual compared with bolus insulin, but bolus

beta-cell function. achieved lower postprandial glucose

and A1C levels.

Replacement therapy with 620 patients with acute myocardial

intensive insulin therapy infarction randomized to intensive

should be used for patients therapy for three or more months

with acute myocardial versus usual therapy demonstrated an

infarction. 11 percent reduction in mortality at

3.4 years of follow-up (number needed

to treat = 9).

Replacement therapy with Single study of 1,548 surgical

intensive insulin therapy intensive care unit patients

should be used for patients randomized to tight control (80 to

in the surgical intensive care 110 mg per dL [4.4 to 6.1 mmol per L])

unit. versus usual control demonstrated

reduced mortality (4.6 percent versus

8.0 percent), and reduced sepsis by

46 percent, dialysis by 42 percent,

and transfusions by 50 percent over

12 months of follow-up.

Replacement therapy with Major anomalies were reduced (1.2

intensive insulin therapy percent versus 10.9 percent) in

should be used for women with diabetic women with tight glycemic

diabetes who are pregnant or control before pregnancy compared with

planning a pregnancy. those referred after six weeks of

gestation.

Macrosomia was associated with

postprandial glucose higher than

130 mg per dL (7.2 mmol per L)

between 29 and 32 weeks of gestation.

Basal therapy with glargine A study compared morning glargine

(Lantus) provides better A1C injection with bedtime glargine

and less nocturnal injection and bedtime NPH. At 24

hypoglycemia when compared weeks, A1C was 7.8, 8.1, and 8.3

with bedtime NPH (Novolin N, percent, respectively; nocturnal

Humulin N). hypoglycemia was 17, 23, and 38

percent, respectively.

Bolus therapy with Patients randomized to bolus therapy

short-acting analogue (lispro with lispro versus regular insulin

[Humalog]) provides no achieved similar A1C and quality of

advantage over regular insulin life, but patients with type 1

(Humulin R) for patients with diabetes report improved treatment

type 2 diabetes, but improves flexibility and satisfaction and less

treatment satisfaction and hypoglycemia. Both achieved lower

lessens hypoglycemia for postprandial glucose levels with

patients with type 1 diabetes. analogue insulin therapy.

Hospitalized patients unable Observational studies show

to take their usual medication sliding-scale therapy using rapid-

should receive basal insulin or short-acting insulin without basal

with periodic bolus insulin results in higher rates of

adjustments. hyperglycemia in hospitalized

patients.

Metformin (Glucophage) Several randomized controlled trials

combined with insulin is demonstrate less weight gain and

preferred to insulin-only hypoglycemia with the addition of

therapy. metformin to insulin therapy.

Insulin plus metformin is cost 188 patients randomized to insulin

effective compared with triple 70/30 plus metformin versus triple

oral medication therapy. oral medication (sulfonylureas,

metformin, thiazolidinediones)

demonstrated equal A1C but lower cost

($3.20 versus $10.40 per day); 14

percent of the triple therapy group

failed treatment and had to start

insulin therapy.

NPH = neutral protamine Hagedorn.

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Patient information: A handout on insulin therapy, written by the authors of this article, is provided on page 511.

See page 425 for definitions of strength-of-recommendation labels.

The Authors

JENNIFER A. MAYFIELD, M.D., M.P.H., is a locum tenens physician and health care research consultant in western Washington. She graduated from Loma Linda University School of Medicine, Loma Linda, Calif., and completed a family practice residency at the University of Minnesota Medical School in Minneapolis, Minn. She was a Robert Wood Johnson Clinical Scholar at the University of Washington School of Medicine, Seattle. She was the epidemiologist for the Diabetes Program of the Indian Health Service for three years and served two years as chair of the American Diabetes Association’s Council on Foot Care and two years on the editorial board of Clinical Diabetes.

RUSSELL D. WHITE, M.D., has a private practice in St. Petersburg, Fla., and is clinical associate professor of family medicine at the University of South Florida College of Medicine in Tampa. He received his medical degree from the University of Missouri-Columbia School of Medicine, Columbia, and completed a family practice residency at the University of Missouri Health Sciences Center, also in Columbia. He has completed two years on the editorial board of Clinical Diabetes. He was a member of the steering committee and program faculty for the American Diabetes Association’s Clinical Education Program in 2003, entitled “Insulin Therapy in the 21st Century.”

Address correspondence to Jennifer A. Mayfield, M.D., M.P.H., 21609 57th Ave. SE, Woodinville, WA 98072 (e-mail: drjenmay@earthlink.net). Reprints are not available from the authors.

JENNIFER A. MAYFIELD, M.D., M.P.H.

Seattle, Washington

RUSSELL D. WHITE, M.D.

University of South Florida College of Medicine, Tampa, Florida

COPYRIGHT 2004 American Academy of Family Physicians

COPYRIGHT 2004 Gale Group