Was insulin review biased, or simply a victim of bad timing?

Commentary

Was insulin review biased, or simply a victim of bad timing?

J Fam Pract. 2007 May;56(5):E1-E4

References

1. Lepore M, Pampanelli S, Fanelli C, et al. 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;49:2142-2148.

2. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000;23:644-649.

3. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004;53:1614-1620.

4. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 2005;28:1107-1112.

5. Meneghini LF, Rosenberg KH, Koenen C, Merilainen MJ, Luddeke HJ. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naïve or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab 2006;8:1-10.

6. Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569-1581.

7. Heise T, Nosek L, Heinemann L, et al. Consistent fast onset of action and absorption of insulin glulisine (GlU) in lean to obese subjects. Diabetes 20005;54(Suppl 1):A145.-

8. 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;49:1163-1168.

9. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T. albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab 2007;9:290-299.

10. Scholtz HE, Pretorius SG, Wessels DH, Becker RH. Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 2005;48:1988-1995.

11. Dornhorst A, Hernandez FO, Koenen C, lüddeke HJ. Initiating insulin detemir improves glycemic control without weight gain in oral antidiabetic drug (OAD)-treated, insulin naive patients with type 2 diabetes: 3-month results from the PREDICTIVE study. Diabetes Med 2006;23 (suppl 4):136.-

12. Rosenstock J, Davis M, Home PD, Larsen J, Tamer SC, Schernthaner G. Insulin detemir added to oral anti-diabetic drugs in type 2 diabetes provides glycemic control comparable to insulin glargine with less weight gain. Diabetes 2006;55 (suppl 1):A132.-

13. Home P, Kurtzhals P. Insulin detemir: from concept to clinical experience. Expert Opin Pharmacother 2006;7:325-343.

14. Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 Diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care 2005;28:260-265.

15. Raskin PR, Hollander PA, Lewin A, Gabbay RA, Bode B, Garber AJ. Basal insulin or premix analogue therapy in type 2 diabetes patients. Eur J Intern Med 2007;18:56-62.

16. Kann PH, Wascher T, Zackova V, et al. Starting insulin therapy in type 2 diabetes: twice-daily biphasic insulin aspart 30 plus metformin versus once-daily insulin glargine plus glimepiride. Exp Clin Endocrinol Diabetes 2006;114:527-532.

17. Ray JA, Valentine WJ, Roze S, et al. Insulin therapy in type 2 diabetes patients failing oral agents: cost-effectiveness of biphasic insulin aspart 70/30 vs. insulin glargine in the US. Diabetes Obes Metab 2007;9:103-113.

18. Valentine WJ, Palmer AJ, Lammert M, Nicklasson L, Foos V, Roze S. Long-term clinical and cost outcomes of treatment with biphasic insulin aspart 30/70 versus insulin glargine in insulin naive type 2 diabetes patients: cost-effectiveness analysis in the UK setting. Curr Med Res Opin 2005;21:2063-2071.

19. Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Järvinen H. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care 2005;28:254-259.

Most importantly, the metabolic profiles of insulin detemir and insulin glargine were identical in a head-to-head comparison,⁹ as was the duration of action of the 2 analogues (both analogues controlled blood glucose over 24 hours). However, insulin detemir showed a lower within-subject variability of its metabolic action,⁹ which had also been demonstrated previously in people with type 1 diabetes.³

In contrast, no advantage of insulin glargine with regard to variability was observed in a similar study in healthy people.¹⁰ In accordance with these experimental findings, insulin detemir was used once daily by the vast majority (81%) of more than 2300 type 2 patients of the predictive study in whom therapy with insulin detemir was initiated in addition to oral antidiabetic agents.¹¹

Thus, both insulin glargine and insulin detemir have a 24-hour duration of action and can be used once daily in people with type 2 diabetes, and they are equally efficient as far as Hb A_1c levels and incidence of hypoglycemia is concerned.¹² Insulin detemir, however, in addition to the potential of reduced within-subject variability, was associated with less weight gain in comparison with both insulin glargine¹² and NPH insulin.¹³

Interestingly, there’s only one short paragraph on the benefits of premixed formulations, containing both a rapid-acting analogue and a protamine-retarded basal insulin analogue (available from Eli Lilly and Novo Nordisk), despite the fact that they:

are widely used
can be applied with an easy dosing algorithm similar to that for insulin glargine^14,15
have been shown to be superior over insulin glargine with regard to Hb A_1c improvement (at slightly higher rates of hypoglycemia) and cost-effectiveness in previously insulin-naïve patients with type 2 diabetes.^14-18

While everybody is certainly welcome to present their viewpoint, it seems important to present all available information—especially when it comes to a CME activity.

Tim Heise, MD
Clinical Science, Profil Institut
für Stoffwechselforschung GmbH, Neuss, Germany

The author responds:

As can be seen from some of the cited references, Dr Heise and his colleagues have been involved in several European clinical insulin trials, including a few^3,7,9 with insulin detemir. The major concern expressed in their letter is an apparent favorable review of insulin glargine at the expense of insulin detemir.

An unavoidable side effect for any published article is that there is invariably a prolonged lag time between preparation of the article, its submission, review, and eventual acceptance for publication. As such, 3 of the references cited in the letter^9,15,17 were not yet published at the time I prepared my review article. In particular, Drs Heise and Brunton cite the article by Klein and colleagues in their discussion of the pharmacokinetic parameters of insulin detemir relative to insulin glargine. Furthermore, one of Dr Brunton’s references¹¹ was not available in either the PubMed or EMBASE databases, which were searched prior to my writing.

Having had the chance to review additional data relative to insulin detemir, I have 3 comments:

I agree with Dr Brunton’s statement that the pharmacologic profiles of insulin detemir and insulin glargine may share more similarities than dissimilarities.
Both long-acting analogs are clearly superior to NPH insulin. Additional head-to-head studies certainly are indicated to see if there are clinical (as opposed to pharmacodynamic) differences that would lead to a preference for selecting either analog.
The observation of less weight gain (less than 1 kg over 52 weeks with insulin detemir as opposed to insulin glargine) is a finding of statistical significance but of doubtful clinical relevance. There is an inherent problem with all insulin therapy—weight change data in studies fail to control for metabolic instability prior to study entrance.

While it is worthwhile to show that both groups had similar A_1c values at study entrance, the final analysis could be affected by the unintended inclusion of a handful of patients with seriously uncontrolled hyperglycemia in either group who have suffered significant weight loss from glycosuria. These individuals will rapidly regain the lost weight once their hyperglycemia is brought under control with exogenous insulin. Studies with insulin evaluating weight change parameters should utilize a protocol including only those individuals with stable weight for several months prior to enrollment.

I also agree with Dr Heise’s concluding statement relative to the importance of presenting all available information. Surprisingly, in his comments regarding premixed insulin he cites the superiority of premixed insulin over insulin glargine in the report from Raskin et al¹⁴ but fails to mention that contained within that same issue of Diabetes Care is a report by Janka and colleagues,¹⁹ who also compared glargine to premixed insulin and found exactly the opposite results.