C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n
Comparison of Basal Insulin Added to
Oral Agents Versus Twice-Daily

Premixed Insulin as Initial Insulin
Therapy for Type 2 Diabetes
clinical practice (5,6). In many patients, ATTHEW C. RIDDLE, MD
insulin treatment is required to achievegood glycemic control (1).
OBJECTIVE — To compare the efficacy and safety of adding once-daily basal insulin versus
initiate insulin treatment in type 2 diabetic switching to twice-daily premixed insulin in type 2 diabetic patients insufficiently controlled by patients is lacking, and treatment regimens are known to vary between countries. Sincemost patients with type 2 diabetes are older RESEARCH DESIGN AND METHODS — In a 24-week, multinational, multicenter,
and physicians’ time is limited, the insulin open, parallel group clinical trial, 371 insulin-naı¨ve patients with poor glycemic control (fasting regimen should be easy to apply. However, blood glucose [FBG] Ն120 mg/dl, HbA 7.5–10.5%) on OADs (sulfonylurea plus metformin) were randomized to once-daily morning insulin glargine plus glimepiride and metformin (glargine plus OAD) or to 30% regular/70% human NPH insulin (70/30) twice daily without monly used, simple regimens for initiating OADs. Insulin dosage was titrated to target FBG Յ100 mg/dl (both insulins) and predinner insulin therapy. One approach consists of blood glucose Յ100 mg/dl (70/30 only) using a weekly forced-titration algorithm.
RESULTS — Mean HbA decrease from baseline was significantly more pronounced (Ϫ1.64 vs.
therapy and initiating two injections of in- Ϫ1.31%, P ϭ 0.0003), and more patients reached HbA Յ7.0% without confirmed nocturnal sulin, often premixed insulin containing a hypoglycemia (45.5 vs. 28.6%, P ϭ 0.0013) with glargine plus OAD than with 70/30. Similarly, FBG decrease was greater with glargine plus OAD (adjusted mean difference Ϫ17 mg/dl [–0.9 mmol/l], P Ͻ 0.0001), and more patients reached target FBG Յ100 mg/dl with glargine plus OAD than with daily. The European Diabetes Policy Group 70/30 (31.6 vs. 15.0%, P ϭ 0.0001). Glargine plus OAD patients had fewer confirmed hypoglycemic episodes than 70/30 patients (mean 4.07 vs. 9.87/patient-year, P Ͻ 0.0001).
patients with type 2 diabetes, insulin ther-apy should be initiated using premixed in- CONCLUSIONS — Initiating insulin treatment by adding basal insulin glargine once daily
sulin twice daily. Nearly 40% of insulin- to glimepiride plus metformin treatment was safer and more effective than beginning twice-dailyinjections of 70/30 and discontinuing OADs in type 2 diabetic patients inadequately controlled are treated with premixed insulin (7). In-deed, a German study has reported that pre- Diabetes Care 28:254 –259, 2005
mixed insulin constitutes the majority(Ͼ80%) of insulin usage in patients withtype 1 and type 2 diabetes (8). Another ap- Theassociationbetweenpoorglyce- with type 1 and type 2 diabetes (1–3); proachincludestheuseofabasalinsulin
cations has been demonstrated in patients from OADs to twice-daily premixed human70/30 insulin versus adding a once-daily in- ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● jection of basal insulin glargine to priorOADs. The method chosen is, similar to From 1Zentralkrankenhaus, Bremen-Nord, Bremen, Germany; the 2Division of Endocrinology, Diabetes,and Clinical Nutrition, Oregon Health and Science University, Portland, Oregon; 3Aventis Pharma Deut- twice-daily premixed insulin, a simple one: schland, Bad Soden, Germany; and the 4Department of Medicine, University of Helsinki, Helsinki, Finland.
insulin glargine has a 24-h time-action pro- Address correspondence and reprint requests to Prof. Hans U. Janka, Zentralkrankenhaus, Bremen-Nord, II Medizinische Abteilung, Hammersbecker Str. 228, 28755 Bremen, Germany. E-mail: can therefore be administered once daily, Received for publication 28 July 2004 and accepted in revised form 20 October 2004.
while glimepiride can be taken once daily H.U.J., M.C.R., and H.Y.-J. have received honoraria and consulting fees from Aventis.
Abbreviations: FBG, fasting blood glucose; OAD, oral antidiabetic agent.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
2005 by the American Diabetes Association.
METHODS — Male or female patients
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. aged 35–75 years with a type 2 diabetes See accompanying editorial, p. 494.
duration of at least 1 year and treated with DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 Janka and Associates
formin for at least 1 month were enrolled the frequency of hypoglycemic events.
at 66 sites in 10 European countries. Fur- ther inclusion criteria included BMI Յ35 mg/dl (5.6 mmol/l), and the before dinner levels Ն120 mg/dl (Ն6.7 mmol/l). Exclu- wise increase of insulin depending on the sion criteria included any additional use Statistical analyses were performed on the glucose Ͼ100 –120 mg/dl, increased by 2 intent-to-treat population, defined as ran- IU/day; blood glucose Ͼ120 –140 mg/dl, one injection of insulin. Statistical testing Ͼ140–160 mg/dl, increased by 6 IU/day; was performed at a significance level of tained for each participating site. All pa- ing two-sided 95% CIs were calculated.
with a 1- to 4-week screening phase and a tests. Statistical analyses were performed ization schedule stratified by center se- recovery after oral carbohydrate, intrave- eligible patients, using a central random- nous glucose, or glucagon administration.
ization service of the electronic case re- 70/30) predinner blood glucose values, as groups can be detected with an ␣ error of 0.05 (two sided) and a ␤ error of 0.2 with RESULTS — A total of 511 patients
dose as before study entry. The dosage of were screened: 371 patients were eligible prised the intent-to-treat population.
visit, patients were randomly assigned to of 4.8 – 6.7%. An eight-point glucose pro- file (before and 2 h after breakfast, lunch, and dinner; at bedtime; and at 3:00 A.M.) fore a visit at baseline and 2, 4, 8, 12, and 24 weeks. The baseline eight-point profile OAD (3 lost to follow-up and 4 other rea- twice daily (before breakfast and dinner), ceiving only glimepiride and metformin.
willing to continue, 5 lack of efficacy, 2 Adverse events were noted by the investi- gator at every visit or telephone contact.
injected using Optipen 1E for insulinglargine and NovoPen for premixed insu- lin. The starting dose for insulin glargine mixed insulin, 10 IU before breakfast and 10 IU before dinner. These starting doses could be lowered if considered clinically to 7.49 Ϯ 1.09% with 70/30 (Fig. 1A).
Յ100 mg/dl (Յ5.6 mmol/l), proportion Mean adjusted HbA1c improvement was doses were adjusted by a forced titration Յ7.0% with no nocturnal hypoglycemia, [95% CI Ϫ1.51 to Ϫ1.78]) than with for 8 weeks and at 2-week intervals there- after for both groups, according to daily self-monitored capillary whole blood glu- ence of Ϫ0.34% (Ϫ0.52 to Ϫ0.16%, P ϭ DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 Glargine plus oral agents vs. premixed insulin
Table 1—Baseline demographics and characteristics of the study population
mg/dl (9.5 to 6.4 mmol/l) with glargineplus OAD and from 172 to 133 mg/dl (9.6to 7.4 mmol/l) with 70/30. Improvement Ϫ24 to Ϫ10 mg/dl [–1.3 to Ϫ0.6 mmol/ l], P Ͻ 0.0001). A greater proportion of Data are means Ϯ SD unless otherwise indicated. OAD refers to sulfonylurea plus metformin.
blood glucose level improved from 182 to137 mg/dl (10.1 to 7.6 mmol/l) in the 0.0003) significantly favored the glargine the 70/30 group (P Ͻ 0.0001 for be- confirmed nocturnal hypoglycemia (P ϭ 70/30 group (P ϭ 0.0596 for the be- tween-treatment difference). Significantly weeks (mean Ϯ SD) in insulin glargineplus glimepiride and metformin (insulinglargine ϩ OADs) and premixed insulintreatment groups. B: Improvement inHbA baseline [before insulin initiation] to endpoint Ϯ SE). DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 Janka and Associates
Figure 2—Twenty-four– hour eight-point blood glucose profiles at baseline (before insulin initiation) and end point in insulin glargine plusglimepiride and metformin (insulin glargine ϩ OADs) and premixed insulin treatment groups (*P Ͻ 0.05 for treatment comparison of changes frombaseline to end point). at the fasting, postlunch, dinner, postdin- ner, and 3:00 A.M. time points (Fig. 2).
was 1.4 Ϯ 3.4 and 2.1 Ϯ 4.2 kg, respec- Insulin dose increased over the study du- tively (P ϭ 0.0805 for between-group CONCLUSIONS — These results
show that in patients with type 2 diabetes dose of 9.9 Ϯ 2.6 to 28.2 Ϯ 15.2 IU at end poorly controlled on oral therapy, adding point for insulin glargine. The prebreak- a single injection of insulin glargine to from the mean starting dose of 10.3 Ϯ 2.5 ilar; 89 patients (50.3%) in the glargine more effective glycemic control than stop- 31.0 Ϯ 16.1 IU at end point, resulting in respiratory disorders (16%), nervous sys- tem disorders (10%), and gastrointestinal patients on 70/30 insulin achieved target per patient-year and the number of events One hundred nine patients (61.6%) re-ceiving glargine plus OAD and 127 pa- Table 2—Mean number of confirmed* hypoglycemic events per patient-years
t i e n t s ( 6 7 . 2 % ) r e c e i v i n g 7 0 / 3 0experienced at least one hypoglycemicevent (P ϭ 0.2838). During treatment, events, expressed as episodes per patient- years, was ϳ50% lower with glargine plus symptomatic, and nocturnal categories(Table 2). Severe hypoglycemia was very *Hypoglycemia was confirmed by blood glucose Ͻ60 mg/dl (3.3 mmol/l). †Severe hypoglycemia wasdefined as symptoms consistent with hypoglycemia that required the assistance of another person and were associated with either a blood glucose level Ͻ36 mg/dl (Ͻ2.0 mmol/l) or prompt recovery after oral carbohydrate or intravenous glucose or glucagon.
DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 Glargine plus oral agents vs. premixed insulin
The relatively low total daily insulin dose 2. Ohkubo Y, Kishikawa H, Araki E, Miyata cemia with the basal insulin regimen is of particular interest because fear of hypo- glycemia remains one of the key obstacles therapy prevents the progression ofdiabetic microvascular complications in to both initiating and optimizing insulin titration to achieve target HbA1c in more therapy (11–13). The difficulty of manag- patients. Even so, some patients will re- ing multiple injections and the associated quire additional prandial injections of in- prospective 6-year study. Diabetes Res Clin sulin to reach the Յ7% HbA1c target.
3. The Diabetes Control and Complications strated that, for patients with type 2 dia- regimen in this study required only a sin- cations Trial. Diabetes 45:1289 –1298,1996 4. Stratton IM, Adler AI, Neil HA, Matthews than starting twice-daily injections of pre- vascular complications of type 2 diabetes regimens for initiating insulin rather than Acknowledgments — This study was sup-
5. European Diabetes Policy Group 1999: A Investigators: Austria: W. Fortunat, A.
desktop guide to type 2 diabetes mellitus.
Holler, R. Prager, J. Thomas, and T. Wascher; Finland: H. Yki-Ja¨rvinen; France: J.F. Blickle, J.M. Brun, M. Rodier, and B. Schmitt; Ger- dards of medical care for patients with di- therapy with premixed insulin (15–17).
many: P. Brommer, K. Busch, H. Dancygier, abetes mellitus (Position Statement).
E.M. Fach, T. Feldmann, A. Fiesselmann, G.
Garanin, J. Grosskopf, J. Habbig, T. Hampel, 7. Koivisto V, Tuominen J, Ebeling P: Lispro H. Herrmann, H.U. Janka, K.A. Jahnke, V.
Jung, M. Kiper, C. Klein, D. Klein, V. Koch, K.
2 diabetic patients. Diabetes Care 22:459 – pared with 70/30 insulin alone. In clinical Langer, E. Lohr, C. Marck, H.J. Marks, P.
Mayr, S. Maxeiner, O. Mueller, F. Odemar, A.
8. Hauner H, Koster L, von Ferber L: Preva- Pfuetzner, H. Pitule, H. Samer, G. Scholz, A.
Sterzing, H.J. Strotmann, J. von Huebbenet, J.
1998 –2001. Dtsch Med Wochenschr 128: Wachter, and U. Wendisch; Italy: A. Civarella, pected to improve the effectiveness of this G. Riccardi, G. Rosti, G. Seghieri, and G.
9. Lepore M, Pampanelli S, Fanelli C, Por- Vespasiani; the Netherlands: R. van Doorn, L.
cellati F, Bartocci L, Di Vincenzo A, Cor- regarding the initiation of insulin therapy Lieverse, and W. Venekamp; Spain: B.F. Go- in patients with type 2 diabetes. The cur- mis, C.F. Hawkins, R.G. Mayor, A. Novials, and J. Zurro Hernandez; Sweden: B. Lindgren ics of subcutaneous injection of long-act- and M. Palmer; Switzerland: P. Gerber; U.K.: R. Bilous, D. Gordon, C.M. Kesson, M. Samp- insulin, and ultralente human insulin and Study team: M. Herbold, C. Kliebe-Frisch, sulin lispro. Diabetes 49:2142–2148, S. Krull, A. Loehr, W. Messer, A. Mueller, H.
clude addressing the benefit of 70/30 in- Nortmeyer, J. Peiker, T. Schlink, and N. Tjia.
sented in abstract form [Diabetes 53 (Suppl.2): action profile of the long-acting insulin formin on the results obtained in the in- A130, 2004 and Diabetelogia 47 (Suppl. 1): sulin glargine–treated group. In addition, A269, 2004] and presented as posters at the with those of NPH insulin and placebo.
American Diabetes Association Scientific Ses- Diabetes Care 23:644 – 649, 2000 sions 2004 and the European Association for 11. Korythowski M: When oral agents fail: the Study of Diabetes Congress 2004.
practical barriers to starting insulin. Int J Obes Relat Metab Disord 26:S18 –S24, ment with all of these regimens, including References
12. Johnson R, Hauber B, Bolinder B: Trade- glycemia in different patient types: results stract). Diabetes 52 (Suppl. 1):A264, 2003 complications in patients with type 2 di- one-half of patients in the glargine plus abetes (UKPDS 33). Lancet 352:837– 853, DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 Janka and Associates
Lahti J, Marjanen T, Niskanen L, Rajala S, insulin regimens in elderly patients with basal insulin: can glargine reduce barrier Ryysy L, Salo S, Seppa¨la¨ P, Tulokas T, Vi- NIDDM. Diabetes Care 19:1326 –1332, to target attainment? (Abstract). Diabetes ikari J, Karjalainen J, Taskinen M-R: Com- parison of insulin regimens in patients with non-insulin-dependent diabetes mellitus.
N Engl J Med 327:1426 –1433, 1992 progress to date. Am J Med 113 (Suppl.
16. Wolffenbuttel BH, Sels JP, Rondas-Col- control but lower weight gain than insulin twice daily in patients with type 2 diabe- 15. Yki-Ja¨rvinen H, Kauppila M, Kujansuu E, tes. Diabetes Metab 28:272–277, 2002 DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005

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