EDITORIAL

Insulin treatment of Type 2 diabetes: a clinical perspective

Some copies of this issue of the Journal of Diabetes are

being distributed in China with a reprint describing the

findings of a consensus conference organized by Novo-

Nordisk on how best to use the combination of 30%

insulin aspart (rapid-acting) and 70% protamine-based

(intermediate-acting) insulin (BIAsp 30).1 The article

offers guidance in approaches to intensifying treatment

with this form of insulin, but does not compare

BIAsp 30 with other insulin treatment regimens, par-

ticularly for people with Type 2 diabetes, a most inter-

esting and important topic.

It is not widely appreciated that the UK Prospective

Diabetes Study (UKPDS) presented evidence that

Type 2 diabetic people receiving either of the sulfo-

nylureas (SU) used for initial treatment had progres-

sively increasing need for addition of insulin over time,

with nearly 10% needing this treatment after 1 year,

and a linear increase to approximately half requiring

this by 6 years.2 Insulin alone was inferior to com-

bined treatment with insulin + SU in maintaining

glycemic control.2 Although one may argue that in the

current era of the availability of multiple oral agents

the use of insulin is less necessary, comparison of max-

imal dose metformin and pioglitazone plus titrated SU

treatment versus metformin plus BIAsp 30 showed that

although either approach could successfully maintain

excellent glycemic control, the former led to both a

greater increase in weight and an increasing frequency

of hypoglycemia.3 Therefore, insulin plus oral agents

may be a preferable approach to thiazolidinedione ⁄SU ⁄metformin combinations for many Type 2 diabetic

people.

Multiple approaches have been shown to be effective

with insulin treatment. The rapid-acting insulin ana-

logs lispro, aspart, and glulisine lead to more physio-

logic replication of the normal postprandial insulin

secretory pattern,4 with a reduction in postprandial

glycemia.5–7 The use of such analogs in combination

with a protamine-containing intermediate-acting insu-

lins led to the development of BIAsp 30 and to the

similar Eli Lilly product, namely protamine-lispro

75% ⁄ lispro 25% (BI-lispro 25), both of which have

the advantage over both intermediate-acting insulin

alone and combinations of regular human insulin plus

intermediate-acting insulin of better reducing postpran-

dial glycemia8,9 while maintaining benefit in overnight

glucose-lowering.10 Furthermore, these preparations

have greater simplicity of administration, with the

potential for a reduced number of injections.

However, one problem with all such protamine-

containing insulin preparations is their pronounced

peak effect, often occurring at an undesirable time

after evening administration,11 so that although effec-

tive in improving glycemia, many studies suggest that

they do so at the expense of a greater likelihood of

nocturnal hypoglycemia than seen with the ‘peakless’

insulin analogs detemir and glargine.12 (It should be

noted that not all authors have reported this finding.13)

Furthermore, intermediate-acting insulin given alone

may not be quite as effective as insulin glargine in low-

ering A1c.14 Detemir appears to have less variability in

overnight glucose-lowering action than seen either with

protamine–intermediate-acting insulin or with insulin

glargine,15 with studies comparing it with intermediate-

acting insulin showing lesser degrees of weight gain.16

The question should then be asked, which is better:

basal insulins, such as protamine-containing prepara-

tions, glargine, or detemir; bolus insulins, particularly

the rapid-acting analogs lispro, aspart, and glulisine;

or the combination insulin preparations BIAsp 30 and

BI-lispro 25? This question was addressed by the

Treating to Target in Type 2 Diabetes (4-T) study.17 A

total of 708 Type 2 diabetic people were randomized

to BIAsp 30, to aspart three times daily before meals,

or to insulin detemir once or twice daily. At 1 year,

the detemir group had a lesser improvement in A1c

but less weight gain, less hypoglycemia, and a lower

total daily insulin dose. After 3 years, when all patients

were moved to a multiple daily insulin (MDI) approach,

hypoglycemia rates remained significantly lower in

those started on insulin detemir and, in addition, these

patients continued to exhibit less weight gain even

though the glycemic improvement was now similar

across all groups. Furthermore, cardiovascular mortal-

ity was significantly lower in the group started on

basal insulin initially and significantly more serious

adverse events occurred in those people initially ran-

domized to BIAsp 30.18

This context should be used in interpreting the

consensus statement of Unnikrishnan et al.1 regarding

intensification of insulin therapy with BIAsp 30. The

authors appropriately suggest that this preparation,

dosed up to three-times daily, may allow improved

glycemic control over basal insulin preparations and

Journal of Diabetes 2 (2010) 65–66

ª 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd 65

present evidence supporting this concept. Although

requiring considerable effort on the parts of both the cli-

nician and the diabetic patient, initial use of basal insulin

titrated to complex basal-bolus MDI regimens may be

preferable to multiple doses of either BIAsp 30 or

BI-Lispro 25, so that one should strongly consider

MDI as the optimal treatment for management of insu-

lin-requiring patients with Type 2 or Type 1 diabetes.

Zachary Bloomgarden

Department of Medicine, Mount Sinai School of

Medicine, New York, NY, USA

Email: zbloom@gmail.com

Andrew Drexler

Gonda (Goldschmied) Diabetes Center,

Los Angeles, CA, USA

Email: adrexler@mednet.ucla.edu

Yehuda Handelsman

Metabolic Institute of America, Tarzana, CA, USA

Email: YHandelsman@pacbell.net

References

1. Unnikrishnan AG, Tibaldi J, Hadley-Brown M et al.

Practical guidance on intensification of insulin therapy

with BIAsp 30: a consensus statement. Int J Clin Pract.

2009; 63: 1571–7.

2. Wright A, Burden AC, Paisey RB, Cull CA, Holman

RR; UK Prospective Diabetes Study Group. Sulfonyl-

urea inadequacy: efficacy of addition of insulin over

6 years in patients with Type 2 diabetes in the UK Pro-

spective Diabetes Study (UKPDS 57). Diabetes Care.

2002; 25: 330–6.

3. Lingvay I, Legendre JL, Kaloyanova PF, Zhang S,

Adams-Huet B, Raskin P. Insulin-based versus triple

oral therapy for newly diagnosed Type 2 diabetes:

which is better? Diabetes Care. 2009; 32: 1789–95.

4. Howey DC, Bowsher RR, Brunelle RL, Woodworth JR.

[Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed

analogue of human insulin. Diabetes. 1994; 43: 396–402.

5. Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW.

Physiological importance of deficiency in early prandial

insulin secretion in non-insulin-dependent diabetes.

Diabetes. 1988; 37: 736–44.

6. Rosenfalck AM, Thorsby P, Kjems L et al. Improved

postprandial glycaemic control with insulin Aspart

in Type 2 diabetic patients treated with insulin. Acta

Diabetol. 2000; 37: 41–6.

7. Dailey G, Rosenstock J, Moses RG, Ways K. Insulin

glulisine provides improved glycemic control in patients

with Type 2 diabetes. Diabetes Care. 2004; 27: 2363–8.

8. Kilo C, Mezitis N, Jain R, Mersey J, McGill J, Raskin

P. Starting patients with Type 2 diabetes on insulin

therapy using once-daily injections of biphasic insulin

aspart 70 ⁄ 30, biphasic human insulin 70 ⁄ 30, or NPH

insulin in combination with metformin. Diabetes

Complications. 2003; 17: 307–13.

9. McSorley PT, Bell PM, Jacobsen LV, Kristensen A,

Lindholm A. Twice-daily biphasic insulin aspart 30

versus biphasic human insulin 30: a double-blind cross-

over study in adults with Type 2 diabetes mellitus. Clin

Ther. 2002; 24: 530–9.

10. Roach P, Yue L, Arora V. Improved postprandial gly-

cemic control during treatment with Humalog Mix25,

a novel protamine-based insulin lispro formulation.

Humalog Mix25 Study Group. Diabetes Care. 1999; 22:

1258–61.

11. 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 com-

parison with those of NPH insulin and placebo. Diabetes

Care. 2000; 23: 644–9.

12. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine

4002 Study Investigators. The treat-to-target trial: ran-

domized addition of glargine or human NPH insulin to

oral therapy of Type 2 diabetic patients. Diabetes Care.

2003; 26: 3080–6.

13. Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M

et al. Insulin glargine or NPH combined with metfor-

min in Type 2 diabetes: the LANMET study. Diabeto-

logia. 2006; 49: 442–51.

14. Fritsche A, Schweitzer MA, Haring HU; 4001 Study

Group. Glimepiride combined with morning insulin

glargine, bedtime neutral protamine hagedorn insulin,

or bedtime insulin glargine in patients with Type 2 dia-

betes. A randomized, controlled trial. Ann Intern Med.

2003; 138: 952–9.

15. Heise T, Nosek L, Rønn 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: 1614–20.

16. Hermansen K, Davies M, Derezinski T, Martinez Ravn

G, Clauson P, Home P. A 26-week, randomized, paral-

lel, treat-to-target trial comparing insulin detemir with

NPH insulin as add-on therapy to oral glucose-lowering

drugs in insulin-naive people with Type 2 diabetes.

Diabetes Care. 2006; 29: 1269–74.

17. Holman RR, Thorne KI, Farmer AJ et al.; 4-T Study

Group. Addition of biphasic, prandial, or basal insulin

to oral therapy in Type 2 diabetes. N Engl J Med.

2007; 357: 1716–30.

18. Holman RR, Farmer AJ, Davies MJ et al.; 4-T Study

Group. Three-year efficacy of complex insulin regi-

mens in Type 2 diabetes. N Engl J Med. 2009; 361:

1736–47.

Editorial

66 ª 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd