Cochrane for Clinicians

Putting Evidence into Practice

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/cochrane/revabstr/AB003287.htm.

Short-Acting Insulin Analogues vs. Human Insulin for Diabetes

Michael Schooff, M.D., and Krista Ehlers, M.D., Clarkson Family Medicine, Omaha, Nebraska

Clinical Scenario

A 63-year-old woman has poor control of her type 2 diabetes with oral medications alone. You decide to discuss insulin therapy with her.

Clinical Question

Are short-acting insulin analogues (lispro, aspart) better than regular insulin for controlling blood sugar levels, reducing A1C levels, and preventing long-term complications of diabetes?

Evidence-Based Answer

For patients with type 2 diabetes, regular insulin and short-acting insulin analogues are equally effective in the treatment of diabetes and in lowering A1C levels. For patients with type 1 diabetes, short-acting analogues produce a slightly greater reduction of A1C levels than regular insulin. Regular insulin and short-acting insulin cause hypoglycemia at similar rates. No studies have compared the effects of regular insulin and insulin analogues on the long-term complications of diabetes.1

Insulin Types and Duration of Action
Insulin type	Onset (minutes)	Peak (hours)	Duration (hours)
Immediate-acting
Insulin lispro solution	15	0.5 to 1.5	2 to 5
Insulin aspart solution	15	1 to 3	3 to 5
Rapid-acting
Regular	30 to 60	2 to 4	8 to 12
Prompt insulin zinc solution	60 to 90	5 to 10	12 to 16
Intermediate-acting
Isophane insulin suspension NPH	60 to 150	4 to 12	24
Lente	60 to 150	7 to 15	24
Long-acting
Ultralente	240 to 480	10 to 30	20 to 36
Lantus	60	5	24 or more
NPH = neutral protamine Hagedorn.

Practice Pointers

Six to 7 million people use insulin or insulin analogues2 in the United States. Patients with type 2 diabetes who maintain tight glucose control have fewer microvascular complications.3 There are many options for the management of insulin in patients with type 1 or type 2 diabetes mellitus. Insulin therapy consists of prandial (bolus) insulin, basal insulin, and correction-dose insulin.4 There are four main types of insulin used for glycemic control: immediate-acting, rapid-acting, intermediate-acting, and long-acting (see accompanying table). Immediate- and rapid-acting insulins are used as bolus insulins; intermediate- and long-acting insulins are used as basal insulins.

Traditional methods of insulin therapy use neutral protamine Hagedorn (NPH) and regular insulin in combination at a ratio of 70:30 taken before morning and evening meals. NPH often is moved to bedtime with regular insulin still taken before the evening meal.2 Another option is prandial insulin with meals in addition to basal insulin once or twice per day. Insulin pumps commonly are used to give continuous subcutaneous insulin.2 One of the benefits of the newer short-acting analogues is their fast onset, which allows patients to take insulin immediately before eating instead of 30 minutes in advance. Also, they enable patients to dose insulin after eating, if needed.1 Disadvantages of short-acting insulin are the high cost and potential long-term side effects. Short-acting insulins are approximately double the cost of regular insulin.2 There also is some concern about the potential mitogenic effects of analogues, and more information is needed on the long-term safety and side effects of these drugs.1

In this Cochrane review,1 Siebenhofer and colleagues looked at regular insulin in comparison with short-acting analogues (lispro, aspart). Overall, they found that short-acting insulin analogues were as effective as regular human insulin in long-term glycemic control, and that they were similarly associated with episodes of hypoglycemia. The only difference found was in patients with type 1 diabetes, who had a small decrease in their A1C levels (about 0.1 percent; 0.2 percent in those who used continuous subcutaneous insulin infusions). It is unlikely that this difference is clinically significant. However, 10 percent of the included studies were only 28 days in duration, and 36 percent of the studies lasted fewer than 90 days. With intensive therapy, A1C levels can begin to drop in three to five weeks,5 but the full effect of a change in therapy may not occur until the end of the 120-day life span of the red blood cells. Thus, more than one third of the included studies may have had insufficient follow-up time to determine the full effect of the intervention on A1C levels.

No studies were found that compared regular insulin with short-acting analogues in terms of their effects on the long-term complications of diabetes. When the results from the Diabetes Control and Complications Trial Research Group study6 are extrapolated, a 0.1 percent reduction in A1C levels translates into a number needed to treat of 650 to prevent the development of diabetic retinopathy, and 765 to halt its progression.

Patients can achieve effective long-term control of blood sugar with regular insulin or a short-acting analogue. Regular and short-acting analogues are similar in achieving glycemic control in studies performed to date. Short-acting analogues may be advantageous in allowing for greater flexibility and convenience. For patients with type 1 diabetes, insulin analogues are slightly more effective than regular insulin, especially if the patient uses an insulin pump.

REFERENCES

1. Siebenhofer A, Plank J, Berghold A, Narath M, Gfrerer R, Pieber TR.
Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev 2004;(4):CD003287.

2. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus. JAMA 2003;289:2254-64.

3. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [published correction appears in Lancet 1999;354:602]. Lancet 1998;352:837-53.

4. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-83.

5. Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A. Correlation of glucose regulation and hemoglobin A1c in diabetes mellitus. N Engl J Med 1976;295:417-20.

6. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.

Cochrane Briefs

Do Tympanostomy Tubes for OME Prevent Hearing Loss?

Clinical Question

Do ventilation tubes prevent hearing loss in children who have otitis media with effusion (OME)?

Evidence-Based Answer

In children with typical hearing and language development, immediate placement of tympanostomy tubes for OME does not improve important long-term outcomes compared with a period of watchful waiting and placement of tubes only if there is no improvement.

Practice Pointers

Children who have OME present with a middle ear effusion but no signs or symptoms of infection. It is thought that because this effusion causes a hearing loss of 20 to 30 decibels (dB) it may negatively impact future hearing and language development. However, because OME is extremely common (affecting an estimated four out of five children before they reach four years of age) and significant speech and hearing problems are rare, the impact of OME may not be so easily determined.

Lous and colleagues performed a systematic review of the literature for randomized controlled trials that compared tympanostomy tubes with no tubes and that included only children who did not have a speech or language delay at baseline. Thirteen studies were identified; randomization varied from ears (e.g., a tube was placed in the right ear but not the left), to time period (immediate insertion of bilateral tubes or a period of watchful waiting), to treatment (adenoidectomy or no adenoidectomy). In three studies, all children underwent adenoidectomy.

In most studies, tubes improved hearing in the short term (about 9 dB at six months and 4 dB at two years). The benefit was attenuated in children who also underwent adenoidectomy (3 to 4 dB at six months and no difference at two years). Differences in speech or language development were minimal or nonexistent. Studies on the adverse effects of tubes are limited but suggest that children given tubes may experience a small long-term hearing loss (mean of 2 to 7 dB) compared with children who have a similar severity of OME but are not given tubes.

MARK H. EBELL, M.D., M.S.

Lous J, et al. Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. Cochrane Database Syst Rev 2004;(4):CD001801.

Room Air vs. Oxygen for Resuscitating Infants at Birth

Clinical Question

Does using 100 percent oxygen for neonatal resuscitation increase morbidity and mortality?

Evidence-Based Answer

Based on limited evidence, it appears that mortality is lower in infants resuscitated with room air than in those given 100 percent oxygen. However, these results should be treated with caution because one fourth of studies used back-up supplementary oxygen.

Practice Pointers

Because excessive oxygen can increase free radical levels and decrease cerebral blood flow, it is thought that it may increase ischemic injury. Many deliveries occur outside of hospitals, where access to oxygen supplementation is limited. In hospital deliveries, early cord clamping often is performed to bring the newborn closer to an oxygen source for resuscitation. Delayed cord clamping has been shown to be beneficial in preterm infants to allow perfusion after delivery.1

Tan and colleagues reviewed the literature to determine whether neonatal resuscitation with room air improves outcomes compared with 100 percent oxygen. They found five randomized and quasirandomized studies including 1,302 infants in total. A reduction in death rate was evident for infants resuscitated with room air (number needed to treat = 20). One study found that infants given room air had better five-minute Apgar scores; however, the difference was small and there were no significant differences in 10-minute Apgar scores or rates of grade 2 or 3 hypoxic ischemic encephalopathy. Another meta-analysis2 came to similar conclusions.

Based on current evidence, 100 percent oxygen should be used with caution during neonatal resuscitation. Routine use of oxygen should not supersede interventions with known benefit such as delayed cord clamping. Evidence supports the routine use of room air.

CLARISSA KRIPKE, M.D.

Tan A, et al. Air versus oxygen for resuscitation of infants at birth. Cochrane Database Syst Rev 2005;(2):CD002273.

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The Authors

Michael Schooff, M.D., is associate director of the Clarkson Family Medicine Residency Program in Omaha. He received his medical degree from the Uniformed Services University of the Health Sciences, F. Hébert School of Medicine, Bethesda, Md., and completed a family medicine residency at Womack Army Medical Center, Fort Bragg, N.C.

KRISTA EHLERS, M.D., is a third-year family medicine resident at the Clarkson Family Medicine Residency Program. She received her medical degree from the University of Nebraska College of Medicine in Omaha.

Address correspondence to Michael Schooff, M.D., Clarkson Family Medicine, 4200 Douglas St., Omaha, NE 68131 (e-mail: mschooff@nebraskamed.com). Reprints are not available from the authors.

REFERENCES

1. Rabe H, Reynolds G, Diaz-Rossello J. Early versus delayed umbilical cord clamping in preterm infants. Cochrane Database Syst Rev 2004;(4):CD003248.

2. Saugstad OD. Room air resuscitation-two decades of neonatal research. Early Hum Dev 2005;81:111-6.

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.

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