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.

In his article “Appropriate use of insulin analogs in an increasingly complex type 2 diabetes mellitus (T2DM) therapeutic landscape” (J Fam Pract 2007; 56: S1–S12) Thomas Flood, MD, provides a nice review of the insulin analogs and their important role in the management of patients with type 2 diabetes mellitus. I believe, however, that the discussion of the pharmacologic properties of the long-acting insulin analogs detemir and glargine may be misleading.

In Figure 2 of the article, the plasma insulin level of insulin glargine is shown to rise to a steady state by 2 hours and remain absolutely constant over 24 hours. Review of the study to which these data are attributed show that the plasma insulin level reaches a maximum of ~22 microunits/mL at 4 hours, decreases slightly to a relatively constant level (~19 microunits/mL) through 13 hours, and then slowly declines to ~15 microunits/ mL at 24 hours.¹ The corresponding plasma glucose level is relatively constant at ~130 mg/dL (the target level of the study) through 15 hours and then progressively rises to ~140 mg/dL at 24 hours.

The study also found that the mean time at which the plasma glucose consistently increased to more than 150 mg/ dL was 22±4 hours, with a mean duration of action of 20.5±3.7 hours, which is somewhat different from the 24 hours cited by Flood in Table 2. While the glucose infusion rate (GIR), which is the rate of glucose infusion needed to maintain the plasma glucose level at a target value, is relatively constant from 4 to 24 hours following injection of insulin glargine, there is some variability.^1,2

In fact, in one of the few direct comparisons of insulin detemir and insulin glargine, in patients with type 1 diabetes mellitus the coefficient of variation for the GIR-AUC_0–24 was 27% vs 48% for insulin detemir and insulin glargine, respectively, while the coefficient of variation for the GIR_max was 23% vs 36%, respectively (P<.001 for all comparisons).³ The results suggest that insulin detemir has a less variable and significantly more predictable glucose-lowering effect than insulin glargine.

The review by Flood also indicates that the duration of action of insulin detemir is 14 hours and that most patients require twice-daily dosing. The duration of insulin detemir is, in fact, dose-dependent ranging from 5.7±6.6 hours at a dose of 0.1 units/kg, 19.9±3.2 hours at a dose of 0.4 units/kg, and 23.2±0.3 hours at a dose of 1.6 units/kg.⁴

As stated by Flood, “Data comparing the pharmacokinetics and efficacy of insulin glargine and insulin detemir are conflicting.” I agree, but the importance of these pharmacologic properties is how they translate into clinical practice. While many clinical trials involving insulin detemir have utilized twice-daily administration, recent studies have demonstrated efficacy with once-daily administration.

For example, one large observational study found that patients treated with insulin detemir experienced a change in mean A_1c from 8.3% at baseline to 7.2% after 3 months, and 79% of patients utilized a once-daily regimen.⁵ Another trial with once-daily insulin detemir before breakfast or bedtime observed similar results.⁶

Thus, it seems fair to say that the pharmacologic profiles of insulin detemir and insulin glargine may share more similarities than dissimilarities, an observation that is supported by recent efficacy data from randomized clinical trials and from large observational studies that more closely resemble actual clinical practice.

Stephen Brunton, MD
Cabarrus Family Medicine Residency Program,
Concord, NC

While it is certainly important to provide information on the “Appropriate use of insulin analogs in an increasingly complex type 2 diabetes mellitus (T2DM) therapeutic landscape,” it is at least equally important to present available information in an unbiased way. The recent article titled as above unfortunately seems as though it may be biased in favor of the analogues of Sanofi-Aventis, the grant supporter of this manuscript.

“Simple algorithms for titration” are provided for both the long-acting and short-acting analogue of Sanofi-Aventis, but the article does not mention that these algorithms can also be applied to competitors’ products. Even though experimental data showed a faster onset of action of insulin glulisine compared with insulin lispro,⁷ no differences whatsoever have been demonstrated between the different short-acting analogues in clinical studies performed so far, neither with regard to diabetes control nor concerning the incidence of hypoglycemia.

As far as basal analogues are concerned, the characteristics and time profiles presented in Table 2 and Figure 2 are either incorrect or incomplete. There are only 2 studies available that have investigated the pharmacodynamic properties of insulin glargine in people with type 2 diabetes.^8,9 Both studies unanimously show that the metabolic effect of insulin glargine shows a slight peak at about 8 to 10 hours post-dosing.