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Narrative Review: A Rational Approach to Starting Insulin Therapy

Arshag D. Mooradian, MD; Marla Bernbaum, MD; and Stewart G. Albert, MD
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From St. Louis University School of Medicine, St. Louis, Missouri.

Acknowledgments: The authors thank the nursing and pharmacy staff and the residents and students training in the Division of Endocrinology, St. Louis University Hospital, for their valuable discussions over many years of caring for people with diabetes.

Grant Support: None.

Potential Financial Conflicts of Interest: Consultancies: A.D. Mooradian (Aventis, Novo Nordisk, Eli Lilly Inc.); Honoraria: A.D. Mooradian (Eli Lilly Inc., Aventis, Novo Nordisk); Grants received: A.D. Mooradian (Novo Nordisk, Eli Lilly Inc., Aventis).

Requests for Single Reprints: Arshag D. Mooradian, MD, Department of Internal Medicine, University of Florida, 653-1 West 8th Street, 4th Floor, LRC, Jacksonville, FL 32209; e-mail, arshag.mooradian@jax.ufl.edu.

Current Author Addresses: Dr. Mooradian: Department of Medicine, University of Florida, 653-1 West 8th Street, 4th Floor, LRC, Jacksonville, FL 32209.

Drs. Bernbaum and Albert: Division of Endocrinology, Saint Louis University Medical School, 1402 South Grand Boulevard, St. Louis, MO 63104.

Ann Intern Med. 2006;145(2):125-134. doi:10.7326/0003-4819-145-2-200607180-00010
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Background: The emergence of multiple insulin products has provided new opportunities to achieve diabetes control. However, the number of options has raised concerns about the optimal choices of products.

Purpose: To briefly review the pharmacologic characteristics of currently available insulin products and to suggest an initial insulin regimen based on common blood glucose profiles among patients with diabetes.

Data Sources: Relevant manuscripts were identified through a MEDLINE search (1996 to 25 February 2006) of the English-language literature. The key phrase used was therapeutic use ofinsulin. The literature search was limited to core clinical journals that have accessible full texts.

Study Selection: Clinical trials and authoritative reviews published between 1996 and February 2006 were selected. A total of 420 manuscripts was reviewed.

Data Extraction: The authors independently reviewed the relevant available literature. This literature, along with the authors' clinical experience, was used to construct practical suggestions.

Data Synthesis: Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial insulin (for example, insulin lispro, insulin aspart, or insulin glulisine) and basal insulin (for example, insulin glargine or insulin detemir), the analogues simulate physiologic insulin profiles more closely than the older conventional insulins. There is currently no strong rationale favoring glargine, neutral protamine Hagedorn insulin, insulin detemir, or fixed-ratio insulin preparations as the preferred agent for initiating insulin therapy.

Limitations: This was a retrospective review of previously published manuscripts chosen at the authors' discretion.

Conclusions: The advent of recombinant DNA technology made it possible to overcome limitations in the time-action profiles of conventional insulins. Insulin therapy must be individualized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. On the basis of the blood glucose profile, the authors suggest an initial insulin regimen that can be used to evaluate individual responsiveness and plan a long-term regimen.




Grahic Jump Location
Figure 1.
The structural modifications of insulin found in insulin analogues.

= Insulin lispro differs from human insulin by the substitution of proline with lysine at position 28 and the substitution of lysine with proline at position 29 of the insulin β chain.

‡ = Insulin aspart is designed with the single replacement of the amino acid proline by aspartic acid at position 28 of the human insulin β chain.

* = Insulin glulisine is designed with the substitution of the amino acid lysine with asparagine at position 3 of the human insulin β chain and by substitution of the amino acid lysine at position 29 with glutamine.

† = Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and 2 arginines are added to the C-terminus of the β chain.

♦ = Insulin detemir is designed to bind albumin in plasma after absorption. Threonine is omitted from position 30 of the insulin β chain and replaced by myristic acid, a C14 fatty acid chain.

Figure reprinted with permission from reference (2): Oiknine R, Bernbaum M, Mooradian AD. A critical appraisal of the role of insulin analogues in the management of diabetes mellitus. Drugs. 2005;65:325-40. [PMID: 15669878]

Grahic Jump Location
Grahic Jump Location
Figure 2.
A suggested protocol for insulin infusion.

Adapted from the protocol that is used at the Saint Louis University Hospital with some modifications. Glucose is obtained with fingerstick unless otherwise specified. The protocol is based on expert opinion and has not yet been validated prospectively.

Grahic Jump Location




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Insulin Therapy and Financial Disclosures
Posted on July 17, 2006
Amnon Schlegel
University of California, San Francisco
Conflict of Interest: None Declared

In publishing the review of insulin therapy by Mooradian and colleagues (1), the Annals of Internal Medicine joins the other three leading general medicine journals, JAMA (2), the New England Journal of Medicine (3), and The Lancet (4) in printing articles about this increasingly important and expensive topic written by paid consultants, grant recipients, and advisors to the manufacturers of the very medications being discussed. These financial ties are disclosed, and readers can draw their own conclusions about a review article that cites only one mortality trial (5) in a bibliography of over 50 articles that are largely industry-sponsored, short term trials using surrogate end points or other review articles written by said trials' authors.

The bigger question is not who writes these articles, but who approves these drugs. As Public Citizen has shown, FDA advisory committees are filled with members with close ties to the drugs being evaluated, and their financial associations lead to voting in favor of applications (6). The FDA advisory committee that reviews the medications discussed by Mooradian et al. has several members with financial ties to insulin analogue manufacturers (7). There is no easy solution to this all pervasive conflict of interest: to argue that these committees be purged of such members may leave us with rooms lacking quorums. Likewise, finding "thought leaders" who are not industry-supported to summarize new pharmacotherapies may be an impossible task.

1. Mooradian AD, Bernbaum M, Albert SG. Narrative review: a rational approach to starting insulin therapy. Ann Intern Med. 2006; 145:125-34.

2. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus. JAMA. 2003;289:2254-2264. [PMID 12734137].

3. Hirsch IB, Insulin analogues. New Engl J Med. 2005; 352:174-83. [PMID: 15647580]

4. Daneman D. Type 1 diabetes. Lancet. 2006; 367:847-58. [PMID: 16530579].

5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86. [PMID: 8366922]

6. Lurie P, Almeida CM, Stine N, Stine AR, Wolfe SM. Financial Conflict of Interest Disclosure and Voting Patterns at Food and Drug Administration Drug Advisory Committee Meetings. JAMA. 2006;295:1921-1928. [PMID 16639051].

7. http://www.fda.gov/cder/audiences/acspage/endocrineroster1.htm

Conflict of Interest:

None declared

PD characteristics need to be updated
Posted on September 8, 2006
Tim Heise
Profil Institute for Metabolic Research
Conflict of Interest: None Declared

Having been involved in many pharmacodynamic (PD) insulin studies, I feel obliged to provide some important updates on the PD characteristics provided in table 1 of the interesting review by Mooradian and colleagues on initiation of insulin therapy that will slightly change the authors' conclusions on treatment strategies. In general, PD characteristics of insulin preparations should be studied in the "real users" [1], i.e. people with type 1 or type 2 diabetes, as, in particular, duration of action tends to be overestimated in nondiabetic individuals [1].

The duration of action of NPH-insulin in type 1 diabetes is approximately 12-13 hours [1, 2] which certainly justifies its classification as intermediate-acting. In contrast, both insulin glargine and insulin detemir showed a significantly longer duration of action of about 20 hours in doses of 0.3-0.4 U/kg [1, 2]. Recent data (S.G. Ashwell et al. Diabetic Medicine 2006; 23: 879"š886) show that insulin glargine has to be used twice daily in some people with type 1 diabetes as it does not cover a whole 24h-period in 15"š30% of patients.

PD data in people with type 2 diabetes (who represent the majority of insulin users) are scarce, but we recently conducted a head-to-head comparison of detemir and glargine that showed almost super-imposable profiles and a dose-dependent duration of action of up to 24 h without relevant differences between these analogues at clinically relevant doses [3]. In addition, we observed a peak metabolic effect with both analogues after 8-12 hours in people with type 2 diabetes [3] and this has recently been confirmed for insulin glargine by the study of Luzio et al. [4]. Thus, in people with type 2 diabetes, the PD characteristics of insulin glargine and insulin detemir do not differ. Therefore, both analogues should be classified as long-acting (as e.g. implemented in the ATC categorization of the WHO) and both analogues should be regarded as equal in the recommended strategies to initiate insulin therapy (table 2 in the review of Mooradian et al.). It is also noteworthy that insulin detemir was shown to be associated with a lower intra-individual variability in PD endpoints in both type 1 and type 2 diabetes [3, 5], and future trials may prove this property to be clinically advantageous.


1. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49(12):2142-8.

2. Plank J, Bodenlenz M, Sinner F, Magnes C, Gorzer E, Regittnig W, Endahl LA, Draeger E, Zdravkovic M, Pieber TR. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005;28(5):1107-12.

3. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T. Insulin Detemir and Insulin Glargine: Similar Time-action Profiles in Subjects with Type 2 Diabetes. Diabetes 2006;55(Suppl.1):A76 (abstract, paper submitted for publication).

4. Luzio S, Dunseath G, Peter R, Pauvaday V, Owens DR. Comparison of the pharmacokinetics and pharmacodynamics of biphasic insulin aspart and insulin glargine in people with type 2 diabetes. Diabetologia. 2006;49:1163-8.

5. Heise T, Nosek L, Ronn BB, Endahl L, Heinemann L, Kapitza C, Draeger E. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53(6):1614-20.

Conflict of Interest:

Tim Heise has received research grants, consultancy payments and/or speaker honoraria from Eli Lilly, Sanofi-Aventis, and Novo Nordisk which are all manufacturers of insulin and insulin analogue preparations.

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