Diabetes Care 28:419-420, 2005
© 2005 by the American Diabetes Association, Inc.
Clinical Care/Education/Nutrition
Brief Report |
Good Glycemic Control With Flexibility in Timing of Basal Insulin Supply
A 24-week comparison of insulin glargine given once daily in the morning or at bedtime in combination with morning glimepiride
Eberhard Standl, MD1,
Stephan Maxeiner, MD2,
Sotirios Raptis, MD (HON)3,
Zahra Karimi-Anderesi, MD4 and
Matthias Axel Schweitzer, MD4 the HOE901/4009 Study Group
1 3 Medical Department, Munich Diabetes Research Institute, Krankenhaus München-Schwabing, Munich, Germany
2 Internist/Diabetologe, Bad Kreuznach-Bosenheim, Germany
3 2nd Department of Internal Medicine, Research Institute and Diabetes Center, Athens University, Atthikon University General Hospital, Athens, Greece
4 Aventis Pharma Deutschland, Bad Soden am Taunus, Germany
Address correspondence and reprint requests to Professor Eberhard Standl, MD, Munich Diabetes Research Institute, 3 Medical Department, Krankenhaus München-Schwabing, Kölner Platz 1, D-80804, Münich, Germany. Email: eberhard.standl{at}lrz.uni-muenchen.de
Abbreviations: FBG, fasting blood glucose
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INTRODUCTION
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The early initiation of insulin therapy to achieve good metabolic control is being increasingly considered in type 2 diabetes (1), but barriers, including fear of hypoglycemia, need to be overcome to achieve target glycemic control (2).
Insulin glargine (glargine; Lantus) is a once-daily, basal human insulin analog. The 24-h duration and flat time-action profile of glargine (3) should give flexibility to patients in terms of the injection time despite targeting fasting blood glucose (FBG) close to normal: administration should be possible at any time of day provided it is at the same time each day. Previously, we have demonstrated similar levels of nocturnal hypoglycemia but better glycemic control with morning versus bedtime glargine plus three milligrams glimepiride (4).
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RESEARCH DESIGN AND METHODS
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The study objective was to compare the frequency of nocturnal hypoglycemia following morning or bedtime administration of glargine plus glimepiride. In a multinational, open-label, randomized study, 624 patients with type 2 diabetes poorly controlled on oral agents received morning or bedtime glargine plus morning glimepiride (2, 3, or 4 mg) for 24 weeks titrated to target FBG  100 mg/dl. Patient demographics and baseline characteristics were similar across the two treatment arms (aged 62.1 vs. 61.5 years, BMI 28.2 vs. 28.7 kg/m2, and diabetes duration 9.5 vs. 10.3 years). The primary outcome, incidence of nocturnal hypoglycemia (hypoglycemia while the patient was asleep, after the evening injection and before rising), was compared using one-sided 95% CIs.
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RESULTS
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The frequency of nocturnal hypoglycemia was equivalent between the groups, with morning glargine noninferior to bedtime (13.0 vs. 14.9%, 95% CI –100 to 2.84%). Most patients who experienced nocturnal hypoglycemia had only one episode (51.3 vs. 54.8%).
At end point, clinically meaningful reductions in HbA1c were observed in both groups: –1.7 ± 1.2%, from 8.8 ± 1.0 to 7.2 ± 1.1% (morning) and –1.6 ± 1.2%, from 8.8 ± 1.0 to 7.2 ± 1.1% (bedtime). A reduction in FBG also occurred: –76.55 ± 50.76 (morning) vs. –80.69 ± 49.41 mg/dl (bedtime) (P = 0.08), with no significant differences in hypoglycemia. The proportion of patients with HbA1c 7.0% was comparable for the two treatment groups (P = 0.66), with 48% (n = 149) and 47% (n = 143) of patients achieving HbA1c 7.0% at end point in the morning and bedtime groups, respectively. Baseline to end point decreases in nocturnal and mean daily blood glucose were similar in both groups (nocturnal blood glucose: –68.64 ± 58.53 vs. –70.10 ± 56.72 mg/dl, P = 0.52; mean daily blood glucose: –73.42 ± 56.55 vs. –68.35 ± 54.45 mg/dl, P = 0.13; all morning versus bedtime). Mean daily insulin dose at end point was comparable between the groups (34.7 ± 17.4 vs. 32.4 ± 17.0 IU, P = 0.15).
Treatment-emergent adverse events were observed in 308 patients, with no clinically relevant between-treatment differences. Possible treatment-related treatment-emergent adverse events occurred in 3.5% of patients (morning: 2.9%; bedtime: 4.1%); 8.0% experienced severe treatment-emergent adverse events (morning: 8.8%; bedtime: 7.3%).
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CONCLUSIONS
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In conclusion, glargine, due to its 24-h action and flat profile, is an appropriate and flexible add-on therapy to start insulin treatment in patients with type 2 diabetes. Flexible dosing with simple glimepiride/glargine regimens achieved significant and practically meaningful improvements in glycemic control, regardless of administration time and without differences in hypoglycemia. This flexibility should facilitate initiation of and adherence to insulin therapy and thus lead to improvements in glycemic control.
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Acknowledgments
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This study was supported by a research grant from Aventis Pharma.
Data from the manuscript have been published in abstract form [Diabetes 52 (Suppl. 1):A134, 2003; Diabetologia 46 (Suppl. 2):A6, 2003] and presented as posters at the American Diabetes Association 2003 and European Association for the Study of Diabetes 2004 congresses and orally at the International Diabetes Federation 2003 congress.
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Footnotes
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E.S. has been a member of an advisory panel for and has received honoraria from Aventis. S.R. has received research/grant support from Aventis.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Received for publication October 18, 2004.
Accepted for publication November 3, 2004.
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References
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- UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998[Medline]
- Korytkowski M: When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord 26(Suppl. 3):S18–S24, 2002
- 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 23:644–649, 2000[Abstract/Free Full Text]
- Fritsche A, Schweitzer MA, Haring HU: Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 138:952–959, 2003[Abstract/Free Full Text]
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INTRODUCTION
RESEARCH DESIGN AND METHODS