368 Article
People with Type 2 Diabetes on Premixed Insulin Therapy: How is the Daily Insulin Dose Partitioned and are there Effects on the Metabolic Control?
Authors
J. Roth1, B. Milke1, N. Müller1, U. Zitterbart2, S. Rechtacek3, T. Rechtacek3, C. Kloos1, G. Wolf1, U. A. Müller1
Affiliations
1
Key words ▶ type 2 diabetes mellitus ● ▶ hemoglobin A1c protein ● ▶ human mixed insulins ● ▶ metabolic diseases ● ▶ primary health care ● ▶ chronic disease ●
Abstract
Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1548796 Exp Clin Endocrinol Diabetes 2015; 123: 368–370 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence U. A. Müller, MD, MSc Endocrinology and Metabolic Disorders Department of Medicine III University Hospital Jena Bachstraße 18 D-07743 Jena Germany Tel.: + 49/3641/934 843 Fax: + 49/3641/933 009 [email protected]
▼
Aim: To investigate the correctness of the recommendation for dose distribution in premixed insulin therapy, with two thirds of daily insulin dose before breakfast and one third of daily insulin dose before dinner. Methods: The individual insulin dose distribution and metabolic control of people with Type 2 diabetes treated with premixed insulin therapy were studied in a cross sectional study involving 199 patients in a university outpatient department and 2 general practices in 2010. Results: All 199 patients were treated with premixed human insulin. The mean pre-breakfast dose was 57 % (min. 32 %, max. 83 %) and the mean pre-dinner dose 43 % (17–67 %) of the total daily insulin. A pre-breakfast dose of exactly two thirds of total daily insulin was used by 6.5 % (n = 13), about two thirds, i. e., 60–70 %,
was injected by 27.6 % of the patients. The diurnal insulin distribution 70 % pre-breakfast insulin did not make any difference in HbA1c, which was 7.3 % (56 mmol/ mol) each. Conclusion: The quite common recommendation in German and Austrian medical textbooks, that premixed insulin therapy should consists of a dose distribution with two thirds before breakfast and one third before dinner, is not observed in daily practice. Diurnal insulin dose distribution and HbA1c are not associated in this cohort. Novelty statement: The circadian insulin dose distribution of 2/3 before breakfast and 1/3 before dinner could not be confirmed for patients with diabetes type 2 and conventional insulin therapy. No correlation between metabolic control and insulin circadian insulin dose distribution was detected.
Introduction
Research Design and Methods
The guideline of the German Diabetes Association [1] recommends for people with Type 2 diabetes on premixed insulin therapy an average daily insulin dose of 0.5–1.0 IU/kg per body weight and to inject roughly two thirds of the daily insulin before breakfast and one third before dinner. However, there are no hard data supporting this recommendation, which also often occurs in German and Austrian medical textbooks [2–6]. Therefore we checked the circadian distribution of insulin in people with Type 2 diabetes who were treated with premixed insulin therapy and their metabolic control regarding to their diurnal dose distribution.
We checked the individual insulin dose distribution in 199 patients with Type 2 diabetes, who were treated with premixed insulin therapy in a university outpatient department in Germany [n = 141; age 72.4 years; 44 % women; time since diagnosis 16.5 years; BMI 32.7 kg/m²; HbA1c 56 mmol/mol (7.2 %) and 2 general practices [n = 58; age 74.7 years; 53 % women; HbA1c 57 mmol/mol (7.4 %)] and their metabolic control from March to October 2010. All Patients were Caucasian. Included were all people with Type 2 diabetes, who were on premixed insulin therapy with human insulin and had an appointment during the observation period. People on a fixed dose regular insulin before breakfast and a fixed dose mixed insulin before dinner (n = 4) were also regarded as premixed insulin therapy. 18 % of the cohort additionally used oral antihyperglycae-
▼
Roth J et al. Circadian Distribution of Insulin Dose … Exp Clin Endocrinol Diabetes 2015; 123: 368–370
▼
Downloaded by: University of Florida. Copyrighted material.
received 07.01.2015 first decision 07.01.2015 accepted 11.03.2015
Department of Internal Medicine III, Jena University Hospital, Jena, Germany Practice for General Medicine, Kranichfeld, Germany 3 Practice for General Medicine, Saalfeld, Germany 2
Article 369
Results
▼
All 199 patients used premixed human insulin. The following insulin mixtures were used 30/70 (91.5 %), 25/75 (5 %), 50/50 (3 %) and 10/90 (0.5 %). Analogue insulines were not used. The mean daily insulin dose was 43.9 IU (8-150 IU) or 0.52 IU/kg body weight (0.10–1.85) in the university outpatient department. In the whole group the mean pre-breakfast dose was 57 % (min. 32 %, max. 83 %) and the mean pre-dinner dose 43 % (min. 17 %, max. 67 %) of the total daily insulin. A pre-breakfast dose of exactly two thirds of total daily insulin had 6.5 % of the patients whereas 27.6 % (n = 55) injected roughly two thirds (60–70 %) ▶ Fig. 1). More people in general practice had a morning dose of ( ● about two thirds than in the university outpatient department (38 % vs. 23 %). There was no difference of HbA1c in people, who were injecting a pre-breakfast doses of up to 60 % in the morning (n = 124, HbA1c = 7.3 % [56.28 mmol/mol]) compared to patients with 60 % up to 70 % (n = 55, HbA1c = 7.3 % [56.28 mmol/mol]) or compared to patients with more than 70 % (n = 20, HbA1c = 7.3 % [56.28 mmol/mol]) morning insulin doses.
60
Number of patients
50
40
30
20
10
0 20.00
40.00 60.00 80.00 100.00 Injected pre-breakfast insulin dose in % of daily dose
120.00
Fig. 1 Distribution of insulin dose before breakfast in percentage of daily dose.
Discussion
▼
Premixed insulin therapy might be considered to be inferior to more complex insulin regimens [7, 8]. The mainly elderly patients in our study were well treated. HbA1c was comparable to the premixed group in the 4T-Study [7] and markedly lower than in the premixed group of the Kumamoto study [9]. Information on the circadian distribution of the insulin doses are neither reported, in the these 2 studies, nor in other important trials with insulin therapy in patients with diabetes Type 2 [10, 11]. Especially in the German and Austrian literature [2–6] it is recommended to split the daily premixed insulin dose to a two third portion in the morning and one third in the evening. We could not find evidence in published data which supports this recommendation. This is one reason, why the recently published national treatment guideline in Germany [12] for the treatment of people with Type 2 diabetes doesn’t even give any recommendation regarding this topic. From this current study the conventional wisdom of an insulin dose distribution of two thirds in the morning and one third in the evening was not supported by data obtained from well-trained elderly patients with type 2 diabetes, who were treated with premixed insulin. Just one fifth of the patients on premixed insulin therapy had about two thirds of the daily insulin dose before breakfast. Differences in HbA1c between patients with two thirds or less or more than two thirds of the daily insulin dose before breakfast could not be seen. One reason for this might be the fact, that the pre-mixed insulin therapy obviously was well adapted to the patient needs by their physicians. On the other hand self-adjustments of insulin dose by the patients could be an explanation. Furthermore the number and carbohydrate content of meals or snacks could explain diurnal changes in insulin dose [13]. Self-adjustment of insulin dose is an integral part of education programs for people with Type 2 diabetes for multiple injection therapy [14] and for pre-mixed insulin therapy [15]. 57 % of the people with premixed insulin therapy adjust their insulin dose with a mean of 5 adjustments per 2 weeks [17]. Severe hypoglycaemia was not observed in any of the patients. Unfortunately mild hypoglycaemia was not registered in this study, but in an follow-up study we found fewer mild hypoglycaemia in people with premixed insulin compared to a flexible pre-prandial regimes with short acting insulin [16]. The standard patient education programme for pre-mixed insulin therapy [20], which was used in all 3 participating institutions, recommends a morning snack 2 h after the breakfast. A lot of patients also prefer a snack in the afternoon. Unfortunately we could not check the number of dose adjustments by the people, nor the number and carbohydrate content of meals. In an earlier survey in our university department 77 % of people with premixed insulin therapy had regularly snacks [13]. In the recent EASD/ADA recommendation [19] an individualization of the therapy for people with Type 2 diabetes is suggested. Complex insulin therapy regimes may stress patients by multiple injections and frequent self-monitoring. In our opinion pre-mixed insulin therapy is simple and safe, could avoid overtreatment and is quite successful in regard to the glycaemic control. The dose adaptation should be done according to patients eating habits and exercise patterns, preferably by the people with Type 2 diabetes themselves and in therapy initiation carefully monitored by trained staff. Explicit recommendations for dose splitting, when pre-mixed insulin therapy is used, seem to be not necessary and should be removed of guidelines and textbooks.
Roth J et al. Circadian Distribution of Insulin Dose … Exp Clin Endocrinol Diabetes 2015; 123: 368–370
Downloaded by: University of Florida. Copyrighted material.
mic drugs (n = 29 metformin, n = 9 sulfonylurea). Data of dose distribution and drugs for diabetes treatment were drawn from the patient records, in case of the university outpatient department the digital patient record EMILTM (www.itcms. de). Documentation of body weight and time since diagnosis was only available for people, who were treated in the university outpatient department. Patients usually attend the clinic or the practices every 3 months to get a new prescription for their drugs, or more often according to clinical needs. Statistical analysis was performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). Associations were considered significant at P ≤ 0.05. HbA1c was analyzed by high performance liquid chromatography (Tosoh, Tokyo, Japan). Each HbA1c was Diabetes Control and Complications Trial (DCCT) adjusted: HbA1c divided by actual mean normal and multiplied by the mean normal HbA1c of the Diabetes Control and Complications Trial percentage; i. e., (5.05 %, 32 mmol/mol).
Contributions
▼
J.R. analyzed the data, contributed to interpretation of finding and wrote the manuscript, B.M. was involved in the conduct of the study, analyzed of the data and contributed to interpretation of findings, N.M. analyzed the data, contributed to interpretation of findings, U.Z., S.R. and U.R. were involved in the conduct of the study in general practice and critically reviewed the manuscript, including interpretation of findings, C.K. and G.W. critically reviewed the manuscript including interpretation of the findings. U.A.M. contributed to the conception and design of the study, contributed to interpretation of finding and critically reviewed the manuscript.
Ethics
▼
An authorization by the Ethics Committee of the University Hospital was not necessary. This was a retrospective analysis of anonymous data.
Fundings
▼
The study was funded by departmental resources.
Disclosures: All authors declare that they have no competing interests regarding this article. References
1 Matthaei S, Bierwirth R, Fritsche A et al. for the German D iabetes Association. Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence based guideline of the German Diabetes Association. Exp Clin Endocrinol Diabetes 2009; 117: 522–557 2 Mühlhauser I, Spraul M, Berger M. Insulinsubstitutionstherapie incl. Insulinpumpentherapie (Insulin supplemention therapy including insulin pump). Berger M, Hrsg. Diabetes mellitus. Urban und Schwarzenberg 1995; 259 3 Mehnert H, Standl E, Usadel K et al. Behandlung mit Insulin (Treatment with insulin). Mehnert H, Hrsg. Diabetologie in Klinik und Praxis. Thieme Verlag 2003; 324 4 Braun J, Dormann Arno J, Braun J., Hrsg. Klinikleitfaden Innere Medizin (Clinical guidelines Internal Medicine). Urban & Fischer 2009; 656 5 Gesenhues S, Ziesché R. Stoffwechsel und Hormonerkrankungen. Gesenhues S, Hrsg. Praxisleitfaden Allgemeinmedizin (Guidelines for General Practise). Urban & Fischer 2010; 966 6 Herold G. Diabetes mellitus. Herold G, Hrsg. Lehrbuch Innere Medizin. Gerd Herold Verlag 2014; 719–747 7 Holman RR, Thorne KI, Farmer AJ et al. for the 4-T Study Group. Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes. N Engl J Med 2007; 357: 1716–1730
8 Kloos C, Sämann A, Lehmann T et al. Flexible, intensive vs. conventional insulin therapy in insulin-naive adults with type 2 diabetes - an openlabel, randomized controlled cross-over clinical trial of metabolic control and patient preference. Diabetes Care 2007; 30: 3031–3032 9 Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomized prospective 5-year study. Diab Res Clin Pract 1995; 28: 103–117 10 Gerstein HC, Miller ME, Byington RP et al. Action to Control Cardiovascular Risk in Diabetes Study Group – Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545–2559 11 Patel A, MacMahon S, Chalmers J et al.ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with Type 2 diabetes. N Engl J Med 2008; 358: 2560–2572 12 Nationale VersorgungsLeitlinie (national treatment guidelinei), Therapie des Typ 2 Diabetes (treatment of Type 2 diabetes), Langfassung (long version), 1. Auflage, August 2013. http://www.versorgungsleitlinien.de/themen/diabetes2/dm2_therapie/pdf/NVL-DM2-Therlang-2.pdf Accessed 16.09.2013 13 Heller T, Kloos C, Keßler D et al. Use of snacks in insulin-treated people with diabetes mellitus and association with HbA1c, weight and quality of life: a cross sectional study. Diabet Med 2015; 32: 353–358 14 Kalfhaus J, Berger M. Insulin treatment with preprandial injections of regular insulin in middle aged type 2 diabetic patients. A two years observational study. Diabetes Metab 2000; 26: 197–201 15 Grüsser M, Bott U, Ellermann P et al. Evaluation of a structured treatment and teaching program for non-insulin-treated type-II-diabetic outpatients in Germany after the nationwide introduction of reimbursment policy for physicians. Diabetes Care 1993; 16: 1268–1275 16 Reise K, Hartung V, Kloos C et al. Inzidenz nicht schwerer Unterzuckerungen bei insulinbehandelten Patienten mit Diabetes mellitus Typ 2 in Abhängigkeit von der Therapieform. (Incidence of non-severe hypoglycaemia in patients with Type 2 Diabetes and Insulin treatment in regard to insulin-regimes). Diab Stoffw 2011; 6 – P155 doi:10.1055/s-0031-1277426 17 Beluchin E, Bäz L, Müller N et al. Frequency of self-adjustment of insulin dose and metabolic control in Type 2 diabetes – is there an association? Diabet Med 2013; 30: e91–e94 doi:10.1111/dme.12071 18 Kloos C, Weimer D, Müller UA. Ernährung bei Patienten mit Diabetes mellitus Typ 2 unter konventioneller (CIT) Therapie mit Mischinsulin und intensivierter Therapie (MIT) mit präprandialem Normalinsulin – eine strukturierte Befragung von nicht selektierten Patienten in einer Hochschulambulanz (FSU Jena) 2004 (Nutrition in patients with Type 2 diabetes with conventional treatment with premixed insulin and intensive treatment with normal insulin – a structured survey of not randomized patients in a university outpatient department (FSU Jena) 2004). Diab Stoffw 2005; 14: Suppl: 61 19 Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patientcentered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; doi:10.1007/s00125-012-2534-0 20 Müller UA, Müller R, Starrach A et al. Should insulin therapy in type II diabetic patients be started on an out- or inpatient basis? Results of a prospective controlled trial using the same treatment and teaching programme in ambulatory care and in a University hospital. Diab Metab (Paris) 1998; 24: 251–255
Roth J et al. Circadian Distribution of Insulin Dose … Exp Clin Endocrinol Diabetes 2015; 123: 368–370
Downloaded by: University of Florida. Copyrighted material.
370 Article
People with Type 2 Diabetes on Premixed Insulin Therapy: How is the Daily Insulin Dose Partitioned and are there Effects on the Metabolic Control?
Authors
J. Roth1, B. Milke1, N. Müller1, U. Zitterbart2, S. Rechtacek3, T. Rechtacek3, C. Kloos1, G. Wolf1, U. A. Müller1
Affiliations
1
Key words ▶ type 2 diabetes mellitus ● ▶ hemoglobin A1c protein ● ▶ human mixed insulins ● ▶ metabolic diseases ● ▶ primary health care ● ▶ chronic disease ●
Abstract
Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1548796 Exp Clin Endocrinol Diabetes 2015; 123: 368–370 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence U. A. Müller, MD, MSc Endocrinology and Metabolic Disorders Department of Medicine III University Hospital Jena Bachstraße 18 D-07743 Jena Germany Tel.: + 49/3641/934 843 Fax: + 49/3641/933 009 [email protected]
▼
Aim: To investigate the correctness of the recommendation for dose distribution in premixed insulin therapy, with two thirds of daily insulin dose before breakfast and one third of daily insulin dose before dinner. Methods: The individual insulin dose distribution and metabolic control of people with Type 2 diabetes treated with premixed insulin therapy were studied in a cross sectional study involving 199 patients in a university outpatient department and 2 general practices in 2010. Results: All 199 patients were treated with premixed human insulin. The mean pre-breakfast dose was 57 % (min. 32 %, max. 83 %) and the mean pre-dinner dose 43 % (17–67 %) of the total daily insulin. A pre-breakfast dose of exactly two thirds of total daily insulin was used by 6.5 % (n = 13), about two thirds, i. e., 60–70 %,
was injected by 27.6 % of the patients. The diurnal insulin distribution 70 % pre-breakfast insulin did not make any difference in HbA1c, which was 7.3 % (56 mmol/ mol) each. Conclusion: The quite common recommendation in German and Austrian medical textbooks, that premixed insulin therapy should consists of a dose distribution with two thirds before breakfast and one third before dinner, is not observed in daily practice. Diurnal insulin dose distribution and HbA1c are not associated in this cohort. Novelty statement: The circadian insulin dose distribution of 2/3 before breakfast and 1/3 before dinner could not be confirmed for patients with diabetes type 2 and conventional insulin therapy. No correlation between metabolic control and insulin circadian insulin dose distribution was detected.
Introduction
Research Design and Methods
The guideline of the German Diabetes Association [1] recommends for people with Type 2 diabetes on premixed insulin therapy an average daily insulin dose of 0.5–1.0 IU/kg per body weight and to inject roughly two thirds of the daily insulin before breakfast and one third before dinner. However, there are no hard data supporting this recommendation, which also often occurs in German and Austrian medical textbooks [2–6]. Therefore we checked the circadian distribution of insulin in people with Type 2 diabetes who were treated with premixed insulin therapy and their metabolic control regarding to their diurnal dose distribution.
We checked the individual insulin dose distribution in 199 patients with Type 2 diabetes, who were treated with premixed insulin therapy in a university outpatient department in Germany [n = 141; age 72.4 years; 44 % women; time since diagnosis 16.5 years; BMI 32.7 kg/m²; HbA1c 56 mmol/mol (7.2 %) and 2 general practices [n = 58; age 74.7 years; 53 % women; HbA1c 57 mmol/mol (7.4 %)] and their metabolic control from March to October 2010. All Patients were Caucasian. Included were all people with Type 2 diabetes, who were on premixed insulin therapy with human insulin and had an appointment during the observation period. People on a fixed dose regular insulin before breakfast and a fixed dose mixed insulin before dinner (n = 4) were also regarded as premixed insulin therapy. 18 % of the cohort additionally used oral antihyperglycae-
▼
Roth J et al. Circadian Distribution of Insulin Dose … Exp Clin Endocrinol Diabetes 2015; 123: 368–370
▼
Downloaded by: University of Florida. Copyrighted material.
received 07.01.2015 first decision 07.01.2015 accepted 11.03.2015
Department of Internal Medicine III, Jena University Hospital, Jena, Germany Practice for General Medicine, Kranichfeld, Germany 3 Practice for General Medicine, Saalfeld, Germany 2
Article 369
Results
▼
All 199 patients used premixed human insulin. The following insulin mixtures were used 30/70 (91.5 %), 25/75 (5 %), 50/50 (3 %) and 10/90 (0.5 %). Analogue insulines were not used. The mean daily insulin dose was 43.9 IU (8-150 IU) or 0.52 IU/kg body weight (0.10–1.85) in the university outpatient department. In the whole group the mean pre-breakfast dose was 57 % (min. 32 %, max. 83 %) and the mean pre-dinner dose 43 % (min. 17 %, max. 67 %) of the total daily insulin. A pre-breakfast dose of exactly two thirds of total daily insulin had 6.5 % of the patients whereas 27.6 % (n = 55) injected roughly two thirds (60–70 %) ▶ Fig. 1). More people in general practice had a morning dose of ( ● about two thirds than in the university outpatient department (38 % vs. 23 %). There was no difference of HbA1c in people, who were injecting a pre-breakfast doses of up to 60 % in the morning (n = 124, HbA1c = 7.3 % [56.28 mmol/mol]) compared to patients with 60 % up to 70 % (n = 55, HbA1c = 7.3 % [56.28 mmol/mol]) or compared to patients with more than 70 % (n = 20, HbA1c = 7.3 % [56.28 mmol/mol]) morning insulin doses.
60
Number of patients
50
40
30
20
10
0 20.00
40.00 60.00 80.00 100.00 Injected pre-breakfast insulin dose in % of daily dose
120.00
Fig. 1 Distribution of insulin dose before breakfast in percentage of daily dose.
Discussion
▼
Premixed insulin therapy might be considered to be inferior to more complex insulin regimens [7, 8]. The mainly elderly patients in our study were well treated. HbA1c was comparable to the premixed group in the 4T-Study [7] and markedly lower than in the premixed group of the Kumamoto study [9]. Information on the circadian distribution of the insulin doses are neither reported, in the these 2 studies, nor in other important trials with insulin therapy in patients with diabetes Type 2 [10, 11]. Especially in the German and Austrian literature [2–6] it is recommended to split the daily premixed insulin dose to a two third portion in the morning and one third in the evening. We could not find evidence in published data which supports this recommendation. This is one reason, why the recently published national treatment guideline in Germany [12] for the treatment of people with Type 2 diabetes doesn’t even give any recommendation regarding this topic. From this current study the conventional wisdom of an insulin dose distribution of two thirds in the morning and one third in the evening was not supported by data obtained from well-trained elderly patients with type 2 diabetes, who were treated with premixed insulin. Just one fifth of the patients on premixed insulin therapy had about two thirds of the daily insulin dose before breakfast. Differences in HbA1c between patients with two thirds or less or more than two thirds of the daily insulin dose before breakfast could not be seen. One reason for this might be the fact, that the pre-mixed insulin therapy obviously was well adapted to the patient needs by their physicians. On the other hand self-adjustments of insulin dose by the patients could be an explanation. Furthermore the number and carbohydrate content of meals or snacks could explain diurnal changes in insulin dose [13]. Self-adjustment of insulin dose is an integral part of education programs for people with Type 2 diabetes for multiple injection therapy [14] and for pre-mixed insulin therapy [15]. 57 % of the people with premixed insulin therapy adjust their insulin dose with a mean of 5 adjustments per 2 weeks [17]. Severe hypoglycaemia was not observed in any of the patients. Unfortunately mild hypoglycaemia was not registered in this study, but in an follow-up study we found fewer mild hypoglycaemia in people with premixed insulin compared to a flexible pre-prandial regimes with short acting insulin [16]. The standard patient education programme for pre-mixed insulin therapy [20], which was used in all 3 participating institutions, recommends a morning snack 2 h after the breakfast. A lot of patients also prefer a snack in the afternoon. Unfortunately we could not check the number of dose adjustments by the people, nor the number and carbohydrate content of meals. In an earlier survey in our university department 77 % of people with premixed insulin therapy had regularly snacks [13]. In the recent EASD/ADA recommendation [19] an individualization of the therapy for people with Type 2 diabetes is suggested. Complex insulin therapy regimes may stress patients by multiple injections and frequent self-monitoring. In our opinion pre-mixed insulin therapy is simple and safe, could avoid overtreatment and is quite successful in regard to the glycaemic control. The dose adaptation should be done according to patients eating habits and exercise patterns, preferably by the people with Type 2 diabetes themselves and in therapy initiation carefully monitored by trained staff. Explicit recommendations for dose splitting, when pre-mixed insulin therapy is used, seem to be not necessary and should be removed of guidelines and textbooks.
Roth J et al. Circadian Distribution of Insulin Dose … Exp Clin Endocrinol Diabetes 2015; 123: 368–370
Downloaded by: University of Florida. Copyrighted material.
mic drugs (n = 29 metformin, n = 9 sulfonylurea). Data of dose distribution and drugs for diabetes treatment were drawn from the patient records, in case of the university outpatient department the digital patient record EMILTM (www.itcms. de). Documentation of body weight and time since diagnosis was only available for people, who were treated in the university outpatient department. Patients usually attend the clinic or the practices every 3 months to get a new prescription for their drugs, or more often according to clinical needs. Statistical analysis was performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). Associations were considered significant at P ≤ 0.05. HbA1c was analyzed by high performance liquid chromatography (Tosoh, Tokyo, Japan). Each HbA1c was Diabetes Control and Complications Trial (DCCT) adjusted: HbA1c divided by actual mean normal and multiplied by the mean normal HbA1c of the Diabetes Control and Complications Trial percentage; i. e., (5.05 %, 32 mmol/mol).
Contributions
▼
J.R. analyzed the data, contributed to interpretation of finding and wrote the manuscript, B.M. was involved in the conduct of the study, analyzed of the data and contributed to interpretation of findings, N.M. analyzed the data, contributed to interpretation of findings, U.Z., S.R. and U.R. were involved in the conduct of the study in general practice and critically reviewed the manuscript, including interpretation of findings, C.K. and G.W. critically reviewed the manuscript including interpretation of the findings. U.A.M. contributed to the conception and design of the study, contributed to interpretation of finding and critically reviewed the manuscript.
Ethics
▼
An authorization by the Ethics Committee of the University Hospital was not necessary. This was a retrospective analysis of anonymous data.
Fundings
▼
The study was funded by departmental resources.
Disclosures: All authors declare that they have no competing interests regarding this article. References
1 Matthaei S, Bierwirth R, Fritsche A et al. for the German D iabetes Association. Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence based guideline of the German Diabetes Association. Exp Clin Endocrinol Diabetes 2009; 117: 522–557 2 Mühlhauser I, Spraul M, Berger M. Insulinsubstitutionstherapie incl. Insulinpumpentherapie (Insulin supplemention therapy including insulin pump). Berger M, Hrsg. Diabetes mellitus. Urban und Schwarzenberg 1995; 259 3 Mehnert H, Standl E, Usadel K et al. Behandlung mit Insulin (Treatment with insulin). Mehnert H, Hrsg. Diabetologie in Klinik und Praxis. Thieme Verlag 2003; 324 4 Braun J, Dormann Arno J, Braun J., Hrsg. Klinikleitfaden Innere Medizin (Clinical guidelines Internal Medicine). Urban & Fischer 2009; 656 5 Gesenhues S, Ziesché R. Stoffwechsel und Hormonerkrankungen. Gesenhues S, Hrsg. Praxisleitfaden Allgemeinmedizin (Guidelines for General Practise). Urban & Fischer 2010; 966 6 Herold G. Diabetes mellitus. Herold G, Hrsg. Lehrbuch Innere Medizin. Gerd Herold Verlag 2014; 719–747 7 Holman RR, Thorne KI, Farmer AJ et al. for the 4-T Study Group. Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes. N Engl J Med 2007; 357: 1716–1730
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