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Using New Insulin Strategies in the
Outpatient Treatment of Diabetes
Clinical Applications
Dawn E. DeWitt, MD, MScDavid C. Dugdale, MD Understanding when to use insulin and how to apply the principles of physi-
ologic insulin replacement using existing and new insulins is a key step to
improving diabetes care. Insulin analogues and premixed insulins increase
with diabetes mellitus (DM)grows, largely due to an epi- physicians’ and patients’ ability to lower hemoglobin A1C levels with fewer
episodes of hypoglycemia. Earlier use of insulin and more aggressive dose
ber of patients treated with insulin will escalation are important steps in achieving treatment goals. This article dis-
cusses using bedtime insulin with oral agents, basal-prandial insulin strat-
egies, and the new insulin analogues.
change these data, newly diagnosedpatients with type 2 DM have less (BOX 1), and misconceptions about the
sulin to oral agents have significantly im- cost and risks of insulin therapy are ma- jor barriers to physician and patient use ticle) is to allow maximum flexibility and basal and prandial insulins simplifies in- basal insulin analogue, insulin glargine, Author Affiliations: Division of General Internal Medi-
A1C levels of less than 7%. A 1990s “Dia- improved physicians’ ability to match pa- cine, Department of Medicine (Drs DeWitt and Dug- dale), University of Washington, Seattle.
tients’ insulin needs. Since physiologic Corresponding Author: Dawn E. DeWitt, MD, MSc,
Rural Clinical School, University of Melbourne, PO Box 6500, Shepparton VIC 3632, Australia (e-mail: Scientific Review and Clinical Applications Section
Editor: Wendy Levinson, MD, Contributing Editor.
We encourage authors to submit papers to “Scien- tific Review and Clinical Applications.” Please con- tact Wendy Levinson, MD, Contributing Editor, JAMA;phone: 312-464-5204; fax: 312-464-5824; e-mail: See also p 2254 and Patient Page.
2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 7, 2003—Vol 289, No. 17 2265
control, the fewest hypoglycemic epi-sodes, and the least weight gain.7 When Insulin Administration
basal insulin is a reasonable first step, Published in: Diabetes Care. 2002;25:S112-S115 especially for a patient who is reluctant to start insulin therapy. A sensible start- Do not mix glargine with other insulin productsWhen mixing rapid-acting insulin and intermediate-acting insulin, inject within Syringe reuse acceptable but meticulous attention to cleanliness is needed; small (BOX 2). The duration of disease for
needles (30 gauge) develop barbed tips easily Injection site should be clean, but wiping with alcohol not needed (insulin injections may be given through clothing) Injection site rotation reduces lipoatrophy but increases variability of absorp- tion (abdomen region has a faster absorption rate than the arm, which is faster than the leg; exercise increases rate of absorption) sulin products. Using generic pricing, the Clinical Practice Recommendations
tient 1 (glyburide, 5 mg twice daily, and Published in: Clinical Practice Recommendations 2002. Diabetes Care. 2002;25: Web site available at: Available as full text at or via ADA Web siteIncludes guidelines for treatment of type 1 and type 2 diabetes mellitus, as well proximately $54 per month for insulinglargine, including syringes and alco- Clinical Guidelines
American Association of Clinical Endocrinologists Web site available at: Web site available at: cost of a treatment program is stronglyinfluenced by the frequency of capillaryblood glucose (CBG) testing ($0.65 pertest). Since basal insulin regimens can of- CLINICAL CASES
Patient 1
buride was reduced to 5 mg, twice daily.
Patient 2
an HbA1C level of 7.8%. He initially lost sulin) or insulin glargine to provide basal ure of an oral agent. He will require in- tive strategy. Limited data show that sul- glucose level. Her diet is high in rice and therapy are very unlikely to reach a tar- tunately, like many other patients, patient 2266 JAMA, May 7, 2003—Vol 289, No. 17 (Reprinted)
2003 American Medical Association. All rights reserved.
USING NEW INSULIN STRATEGIES IN THE OUTPATIENT TREATMENT OF DIABETES tient mixes the insulin) NPH/R or Ul-tralente (insulin zinc extended) (UL)/R, Box 2. Starting Basal Insulin
Starting basal insulin (bedtime NPH or glargine): use an initial dose of 10 to 20 U or 0.1 to 0.2 U/kg (a higher dose can be used for poorly controlled patients) Adjusting basal insulin: increase the dose by 4 U if fasting CBG level is higher than 140 mg/dL (7.8 mmol/L) on 3 consecutive measures or by 2 U if fasting CBG level is 110 to 140 mg/dL (6.1-7.8 mmol/L) on 3 consecutive measures Most patients with type 2 diabetes mellitus need a total daily dose of 1 to 1.2 U/kg mix regimen because the tail of the regu- to achieve a hemoglobin A1C level less than 7% (basal dose 0.5-0.6 U/kg perday) lar insulin action overlaps with the peak Converting from an existing regimen: divide total daily insulin need by 2 and use NPH action in late morning and at night.
that as the basal dose (some experts recommend decreasing the starting basal dose by 20% to decrease the risk of hypoglycemia). Alternatively, in a patient already taking NPH or Ultralente who is being switched to insulin glargine, lin and prandial regular insulin, who are use approximately 80% of the NPH or Ultralente dose as glargine CBG, capillary blood glucose; NPH, neutral protamine Hagedorn (isophane insulin).
glycemic control, have wide fluctua-tions of glucose levels with very high glu-cose levels immediately after breakfastand dinner and hypoglycemia beforelunch and at night. This risk of night- Figure 1. Example of Insulin Replacement With Premix 75% NPL /25% Lispro Regimen
time hypoglycemia is the reason for thetraditional bedtime snack. The pre- lin lispro protamine; NPL)/lispro (L) in-sulin analogue combination (75% NPL/25% L) is a good option for patients with high-carbohydrate diets or who experi-ence prelunch hypoglycemia. InsulinNPL has a peak similar to that of NPH, but the shorter duration of action of in-
sulin lispro, compared with regular in-
sulin, means less overlap (FIGURE 1) and
Rapid-acting insulin (lispro) more closely matches the effect of normal insulin on carbohydrate disposal and causes fewer episodes of hypoglycemia. Many patients using this regimen need supplemental rapid-actinginsulin at lunch (not shown). Lispro is a rapid-acting and NPL is an intermediate-acting insulin. Arrows indicate insulin injection; NPL, neutral protamine lispro (insulin lispro protamine).
her HbA1C levels from 8.5% to 6.2% withfewer episodes of hypoglycemia becausethis regimen better matched her needs.
lin name in full. Furthermore, use of the abbreviation “U” for units may be mis- translated to 50, if not written clearly.
Patient 3
physicians use the abbreviations “R” for takes 70% N/30% R insulin, twice daily.
regular, “N” for NPH, or “L” for Lente level of precision. Finally, most patients pro; “N” can mean “NovoLog” (Novo Nordisk, Princeton, NJ), NPL, or NPH.
2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 7, 2003—Vol 289, No. 17 2267
USING NEW INSULIN STRATEGIES IN THE OUTPATIENT TREATMENT OF DIABETES Figure 2. Example of Insulin Stacking With Premix 70% NPH/30% Regular Regimen
a meal. These insulins are called rapid-acting insulins because they begin to act in 5 to 15 minutes, peak at 30 to 90 min- utes, and remain in the body for 5 hours.
ments using an insulin algorithm thatuses their usual insulin dose, current CBG level, and expected exercise andfood consumption. Although the pro-tein and fat content of a meal are impor- tant, it is the carbohydrate content thathas the greatest influence on patients’ glu- cose levels and insulin needs. The car-bohydrate content of foods can be eas- Insulin stacking, administering injections too close together in time, of any type of insulin results in hypogly- ily determined from food labels. A typical cemia if patients already have reasonable glycemic control. As depicted in the figure, the additive effect of theinsulin profile explains why patients would experience episodes of evening or nighttime hypoglycemia and fasting hyperglycemia. Arrows indicate insulin injection; NPH, neutral protamine Hagedorn (isophane insulin).
unit of rapid-acting prandial insulin (lis-pro or aspart) per 10 to 15 g of carbo- need ratios of 1 U insulin for every 3 to This patient’s erratic schedule and pat- terns of insulin use have resulted in insu- lin glargine causes fewer serious adverse (FIGURE 2). The concept of “basal-
gain (1 kg less at 28 weeks).6 Lastly, one prandial” physiologic insulin dosing (see significantly better patient treatment sat- CBG level of patient 3 is 250 mg/dL (13.9 helps improve patients’ understanding of their diabetes, significantly increases flex- ibility for patients since they can change they did while using either single- or mul- mmol/L), plus 4 U at 1 U per 15 g of car- bohydrate; a total of 6 U of prandial insu- fore can be confused with other clear in- flexibility,20 it may be too complicated for some patients. Alternatively, insulin dos- the plasma glucose level. Therefore, basal- carbohydrates or calories at each meal.
prandial regimen doses are one-half basal jor considerations affecting the dose are glargine is peakless with a 20- to 24-hour duration of action, and thus can be given of NPH or glargine at bedtime (Box 2).
Persistence in adjusting insulin doses to Patient 4
reach target CBG levels is essential.
since they can be given as a mealtime in- 2268 JAMA, May 7, 2003—Vol 289, No. 17 (Reprinted)
2003 American Medical Association. All rights reserved.
USING NEW INSULIN STRATEGIES IN THE OUTPATIENT TREATMENT OF DIABETES sone. Short-acting secretagogues (eg, re- Thompson TJ, Narayan KM. A diabetes report card forthe United States: quality of care in the 1990s. Ann paglinide) or additional long-acting oral Intern Med. 2002;136:565-574.
6. Rosenstock J, Schwartz SL, Clark CM Jr, Park GD,
Donely DW, Edwards MB. Basal insulin therapy in type2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24: 631-636.
7. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T,
treatment for patient 5 is low. It is likely Vanamo R, Hekkila M. Comparison of bedtime insu- lin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med. 1999;130:389-396.
8. Yki-Jarvinen H, Dressler A, Ziemen M. Less noc-
turnal hypoglycemia and better post-dinner glucosecontrol with bedtime insulin glargine compared with dial insulin alone will be sufficient since bedtime NPH insulin during insulin combination therapy ing, is usually the easiest treatment plan.
in type 2 diabetes: HOE 901/3002 Study Group. Dia-betes Care. 2000;23:1130-1136.
9. Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca
they are fasting and it is adjusted based sulin lispro or aspart are ideal agents in TE, Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes: US StudyGroup of Insulin Glargine in Type 1 Diabetes. Diabe- 10. Annuzzi G, Del Prato S, Arcari R, et al. Prepran-
dial combination of lispro and NPH insulin improves
tions and, typically, by decreased physi- overall blood glucose control in type 1 diabetic pa- cal activity. Patients’ prandial insulin tients: a multicenter randomized crossover trial. Nutr Metab Cardiovasc Dis. 2001;11:168-175.
11. Holmboe ES. Oral antihyperglycemic therapy for
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12. Wright A, Burden AC, Paisey RB, Cull CA, Hol-
Patient 5
man RR, the UK Prospective Diabetes Group. Sulfo- nylurea inadequacy: efficacy of addition of insulin over6 years in patients with type 2 diabetes in the UK Pro- spective Diabetes Study (UKPDS 57). Diabetes Care.
13. Malone JK, Yang H, Woodworth JR, et al. Huma-
log Mix25 offers better mealtime glycemic control in
patients with type 1 or type 2 diabetes. Diabetes tion is glyburide, 7.5 mg/d. Typical fast- Metab. 2000;26:481-487.
14. Malone JK, Woodworth JR, Arora V, et al. Im-
ing CBG levels are 100 to 130 mg/dL (5.6- proved postprandial glycemic control with Humalog Mix75/25 after a standard test meal in patients with type2 diabetes mellitus. Clin Ther. 2000;22:222-230.
prandial insulin strategies are easy to use 15. Roach P, Strack T, Arora V, Zhao Z. Improved gly-
and often improve patients’ understand- caemic control with the use of self-prepared mix- tures of insulin lispro and insulin lispro protamine sus-pension in patients with types 1 and 2 diabetes. Int crease dosing and mealtime flexibility.
J Clin Pract. 2001;55:177-182.
16. Abraira C, Henderson WG, Colwell JA, et al. Re-
Acknowledgment: We thank Irl B. Hirsch, MD, for his
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2003 American Medical Association. All rights reserved.
(Reprinted) JAMA, May 7, 2003—Vol 289, No. 17 2269


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