- Email: [email protected]
Waist circumference reduction after insulin detemir therapy in type 2 diabetes patients previously treated with NPH
diabetes research and clinical practice 84 (2009) e18–e20
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres
Brief report
Waist circumference reduction after insulin detemir therapy in type 2 diabetes patients previously treated with NPH§ E. Mandosi, M. Fallarino, M. Rossetti, A. Gatti, S. Morano * Department of Clinical Sciences, ‘‘Sapienza’’ University, Rome, Italy
article info
abstract
Article history:
We studied the weight-sparing effect and treatment satisfaction when switching from NPH
Received 22 December 2008
to insulin detemir in type 2 diabetes. Mean HbA1c (P < 0.05) and waist circumference
Received in revised form
(P < 0.05) were reduced while treatment satisfaction improved (P < 0.03). No weight gain
22 December 2008
was observed. Detemir improves glycemic control, treatment satisfaction, and may provide
Accepted 9 February 2009
additional weight-sparing benefits.
Published on line 17 March 2009
# 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Insulin therapy Insulin detemir NPH insulin Type 2 diabetes
1.
Introduction
The importance of glycemic control in reducing the incidence and progression of micro- and macrovascular complications in type 2 diabetes is well-documented, [1], and insulin therapy is often required to achieve and maintain recommended levels of glycemic control (glycosylated haemoglobin [HbA1c] <7%, [2]) as beta-cell function declines [3]. Weight gain associated with insulin therapy often delays insulin initiation and may adversely affect self-esteem in patients with diabetes who are already overweight [4]; some patients omit insulin dose in order to minimize weight change [4,5]. In addition to exacerbating patient barriers to insulin, increased weight may potentiate clinical risk factors in diabetes. It has been long recognized that a high BMI §
contributes to the development of insulin resistance; in particular, abdominal weight distribution in patients with type 2 diabetes has been shown to be associated with impaired fibrinolysis and thrombinogenesis elevation [6]. Obesity is one of the defining features of the metabolic syndrome, which usually refers to a series of cardiovascular risk factors occurring in the context of an impaired insulin response, and which may potentiate development of diabetes-related complications [7]. Insulin detemir (detemir, Levemir1, Novo Nordisk, Bagsværd, Denmark) is a long-acting basal insulin analog available for the treatment of type 1 and type 2 diabetes; it is soluble at neutral pH and is able to bind reversibly to albumin after injection [8]. In clinical trials, detemir treatment was associated with reduced risk of hypoglycemia and less weight
This trial was registered at ClinicalTrials.gov, trial number NCT00714844. * Corresponding author at: ‘‘Sapienza’’ University, Department of Clinical Sciences – Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico, 155 – 00161 Rome, Italy. Tel.: +39 06 49978381; fax: +39 06 49978381. E-mail address: [email protected] (S. Morano). 0168-8227/$ – see front matter # 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2009.02.006
diabetes research and clinical practice 84 (2009) e18–e20
gain in comparison with NPH insulin (NPH, Protaphane, Novo Nordisk, Bagsværd, Denmark) in type 1 and type 2 diabetes [9– 11], and data from observational studies support these benefits in clinical practice [12,13]. These findings suggest that detemir could be well tolerated when added to oral antidiabetic drugs (OADs) in people with inadequately controlled type 2 diabetes. The aim of this study was to evaluate the effect of detemir treatment on glycemic control, anthropometric parameters and treatment satisfaction in patients with type 2 diabetes not well controlled with NPH administration.
2.
Research design and methods
Twenty patients with type 2 diabetes (13 male, 7 female, aged 59.4 9.1 years, body mass index [BMI] 31.5 6.4 kg/m2, HbA1c 8.5 1.0%) requiring basal insulin replacement and previously treated with NPH insulin were recruited. The study protocol was approved by the local ethics committee. Inclusion criteria were a duration of type 2 diabetes for at least 12 months, a BMI <40 kg/m2 and HbA1c >7.5%. Patients satisfying the inclusion criteria had their treatment with NPH insulin administered once daily replaced with detemir administered once daily too at bed-time for 20 weeks. The switch from NPH to detemir was done on a unit-to-unit basis and the dose of detemir was adjusted to achieve glycemic targets as recommended. OAD dose remained unchanged in all patients. At baseline and after treatment, patients underwent the following investigations: physical examination, blood sampling (following overnight fasting) for measurement of glucose, lipid profile (total, HDL and LDL cholesterol, triglycerides), liver function tests (alanine aminotransferase-ALT and aspartate aminotransferase AST) and HbA1c. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was also completed.
3.
Results
In all patients no significant difference was found in insulin dose required between the initial and final visit (12 7 U [0.1 0.4 U/kg] vs 13 5 U [0.1 0.2 U/kg], P = 0.24) and no major hypoglycaemic episodes were recorded during the study. After 20 weeks of detemir therapy, there was a significant reduction in HbA1c (from 8.5 1.3 to 7.9 1.2%, P < 0.05) and waist circumference (from 107.0 13.4 to 102.2 10.5 cm, P < 0.05) and a significant increase in treatment satisfaction (measured by DTSQ) (from 38.9 7.0 to 30.3 9.5, P < 0.03). Furthermore, no weight gain was observed in patients treated with detemir versus NPH (BMI was 31.6 6.5 at baseline and 30.5 6.0 kg/m2 at 20 weeks, P = 0.29, weight was 88.9 16.7 kg at baseline 85.1 15.0 kg at 20 weeks, P = 0.22). Finally no differences in total (185.5 35.2 vs 175.0 47.3 mg/dl), HDL cholesterol (46.2 11.0 vs 45.2 10.8 mg/dl), tryglicerides (157.0 78.7 vs 138.2 48.2 mg/dl), ALT (22.6 8.3 vs 19.5 6.5 U/l) and AST (32.2 19.1 vs 26.2 12.0) values has been observed.
4.
e19
Discussion
In this study we demonstrated that type 2 diabetes patients switched from NPH to detemir had improved metabolic control and reduced waist circumference after 20 weeks. Moreover patients reported an improvement in treatment satisfaction using the standardised DTSQ. As shown HbA1c value was reduced after insulin detemir treatment, despite no significant increase in the insulin or OAD dose. This effect could be explained by a better adherence to diet. However it remains to investigate whether detemir was able to reduce food intake. In addition to benefits of glycemic control and tolerability [10] detemir has, uniquely, been reported to result in less weight gain compared with other basal insulins such as NPH and glargine [14,15]. Our data support this finding, as weight change was negligible throughout the study despite the improvement in glycemic control. The effect seen on waist circumference was investigated for the first time in this population and it is of interest because high waist circumference, due to visceral fat deposition, represents one component of metabolic syndrome. In patients with type 2 diabetes, metabolic syndrome is thought to associate with increased cardiovascular risk [6]. Since the interplay of contributory factors are still poorly understood [7], metabolic syndrome is currently treated by addressing each component factor; further research is needed to determine whether detemir has the potential to influence cardiovascular risk via its reduced propensity for causing weight gain in comparison with alternative insulins.
Conflict of interest The authors state that they have no conflict of interest.
references
[1] 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 (UKPD33), Lancet 352 (1998) 837–853. [2] D.M. Nathan, J.B. Buse, M.B. Davidson, E. Ferrannini, R.R. Holman, R. Sherwin, et al., Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes, Diabetologia 49 (2006) 1711–1721. [3] R.R. Holman, K.I. Thorne, A.J. Farmer, M.J. Davies, J.F. Keenan, S. Paul, et al., Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes, N. Engl. J. Med. 357 (2007) 1716–1730. [4] M. Korytkowski, When oral agents fail: practical barriers to starting insulin, Int. J. Obes. 26 (2002) S18–24. [5] K. Bryden, A. Neil, R.A. Mayou, R.C. Peveler, C.G. Fairburn, D.B. Dunger, Eating habits, body weight and insulin misuse, Diabetes Care 22 (1999) 1959–1960. [6] E. Kozek, B. Katra, M. Malecki, J. Sieradzki, Visceral obesity and hemostatic profile in patients with type 2 diabetes: the
e20
[7]
[8] [9]
[10] [11]
[12]
diabetes research and clinical practice 84 (2009) e18–e20
effect of gender and metabolic compensation, Rev. Diabet. Stud. 1 (2004) 122–128. J. Wang, S. Ruotsalainen, L. Moilanen, P. Lepisto, M. Laakso, J. Kuusisto, The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns, Eur. Heart J. 28 (2007) 857–865. P. Kurtzhals, Pharmacology of insulin detemir, Endocrinol. Metab. Clin. North. Am. 36 (Suppl. 1) (2007) 14–20. A. Dornhorst, H.J. Lu¨ddeke, S. Sreenan, P. Kozlovski, J.B. Hansen, B.J. Looij, et al., Insulin detemir improves glycaemic control without weight gain in insulin-naı¨ve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE(TM) study, Int. J. Clin. Pract. 62 (2008) 659–665. T.M. Chapman, C.M. Perry, Spotlight on insulin detemir in type 1 and 2 diabetes mellitus, BioDrugs 19 (2005) 67–69. P. Home, P. Kurzhals, Insulin detemir: from concept to clinical experience, Expert Opin. Pharmacother. 7 (2006) 325–343. A. Dornhorst, H.-J. Lu¨ddeke, S. Sreenan, C. Koenen, J.B. Hansen, A. Tsur, et al., Safety and efficacy of insulin
detemir in clinical practice: 14-week follow-up data from type 1 and type 2 diabetes patients in the PREDICTIVETM European cohort, Int. J. Clin. Pract. 61 (2007) 523–528. [13] A. Dornhorst, H.J. Lu¨ddeke, C. Koenen, M. Merila¨inen, A. King, A. Robinson, et al., Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE, Diabetes Obes. Metab. 10 (2008) 75–81. [14] K. Hermansen, M. Davies, Does insulin detemir have a role in reducing risk of insulin-associated weight gain? Diabetes Obes. Metab. 9 (2007) 209–217. [15] J. Rosenstock, M. Davies, P.D. Home, J. Larsen, C. Koenen, G. Shernthaner, A randomized, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when added to glucose-lowering drugs in insulin-naive people with type 2 diabetes, Diabetologia 51 (2008) 408–416.
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres
Brief report
Waist circumference reduction after insulin detemir therapy in type 2 diabetes patients previously treated with NPH§ E. Mandosi, M. Fallarino, M. Rossetti, A. Gatti, S. Morano * Department of Clinical Sciences, ‘‘Sapienza’’ University, Rome, Italy
article info
abstract
Article history:
We studied the weight-sparing effect and treatment satisfaction when switching from NPH
Received 22 December 2008
to insulin detemir in type 2 diabetes. Mean HbA1c (P < 0.05) and waist circumference
Received in revised form
(P < 0.05) were reduced while treatment satisfaction improved (P < 0.03). No weight gain
22 December 2008
was observed. Detemir improves glycemic control, treatment satisfaction, and may provide
Accepted 9 February 2009
additional weight-sparing benefits.
Published on line 17 March 2009
# 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Insulin therapy Insulin detemir NPH insulin Type 2 diabetes
1.
Introduction
The importance of glycemic control in reducing the incidence and progression of micro- and macrovascular complications in type 2 diabetes is well-documented, [1], and insulin therapy is often required to achieve and maintain recommended levels of glycemic control (glycosylated haemoglobin [HbA1c] <7%, [2]) as beta-cell function declines [3]. Weight gain associated with insulin therapy often delays insulin initiation and may adversely affect self-esteem in patients with diabetes who are already overweight [4]; some patients omit insulin dose in order to minimize weight change [4,5]. In addition to exacerbating patient barriers to insulin, increased weight may potentiate clinical risk factors in diabetes. It has been long recognized that a high BMI §
contributes to the development of insulin resistance; in particular, abdominal weight distribution in patients with type 2 diabetes has been shown to be associated with impaired fibrinolysis and thrombinogenesis elevation [6]. Obesity is one of the defining features of the metabolic syndrome, which usually refers to a series of cardiovascular risk factors occurring in the context of an impaired insulin response, and which may potentiate development of diabetes-related complications [7]. Insulin detemir (detemir, Levemir1, Novo Nordisk, Bagsværd, Denmark) is a long-acting basal insulin analog available for the treatment of type 1 and type 2 diabetes; it is soluble at neutral pH and is able to bind reversibly to albumin after injection [8]. In clinical trials, detemir treatment was associated with reduced risk of hypoglycemia and less weight
This trial was registered at ClinicalTrials.gov, trial number NCT00714844. * Corresponding author at: ‘‘Sapienza’’ University, Department of Clinical Sciences – Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico, 155 – 00161 Rome, Italy. Tel.: +39 06 49978381; fax: +39 06 49978381. E-mail address: [email protected] (S. Morano). 0168-8227/$ – see front matter # 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2009.02.006
diabetes research and clinical practice 84 (2009) e18–e20
gain in comparison with NPH insulin (NPH, Protaphane, Novo Nordisk, Bagsværd, Denmark) in type 1 and type 2 diabetes [9– 11], and data from observational studies support these benefits in clinical practice [12,13]. These findings suggest that detemir could be well tolerated when added to oral antidiabetic drugs (OADs) in people with inadequately controlled type 2 diabetes. The aim of this study was to evaluate the effect of detemir treatment on glycemic control, anthropometric parameters and treatment satisfaction in patients with type 2 diabetes not well controlled with NPH administration.
2.
Research design and methods
Twenty patients with type 2 diabetes (13 male, 7 female, aged 59.4 9.1 years, body mass index [BMI] 31.5 6.4 kg/m2, HbA1c 8.5 1.0%) requiring basal insulin replacement and previously treated with NPH insulin were recruited. The study protocol was approved by the local ethics committee. Inclusion criteria were a duration of type 2 diabetes for at least 12 months, a BMI <40 kg/m2 and HbA1c >7.5%. Patients satisfying the inclusion criteria had their treatment with NPH insulin administered once daily replaced with detemir administered once daily too at bed-time for 20 weeks. The switch from NPH to detemir was done on a unit-to-unit basis and the dose of detemir was adjusted to achieve glycemic targets as recommended. OAD dose remained unchanged in all patients. At baseline and after treatment, patients underwent the following investigations: physical examination, blood sampling (following overnight fasting) for measurement of glucose, lipid profile (total, HDL and LDL cholesterol, triglycerides), liver function tests (alanine aminotransferase-ALT and aspartate aminotransferase AST) and HbA1c. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was also completed.
3.
Results
In all patients no significant difference was found in insulin dose required between the initial and final visit (12 7 U [0.1 0.4 U/kg] vs 13 5 U [0.1 0.2 U/kg], P = 0.24) and no major hypoglycaemic episodes were recorded during the study. After 20 weeks of detemir therapy, there was a significant reduction in HbA1c (from 8.5 1.3 to 7.9 1.2%, P < 0.05) and waist circumference (from 107.0 13.4 to 102.2 10.5 cm, P < 0.05) and a significant increase in treatment satisfaction (measured by DTSQ) (from 38.9 7.0 to 30.3 9.5, P < 0.03). Furthermore, no weight gain was observed in patients treated with detemir versus NPH (BMI was 31.6 6.5 at baseline and 30.5 6.0 kg/m2 at 20 weeks, P = 0.29, weight was 88.9 16.7 kg at baseline 85.1 15.0 kg at 20 weeks, P = 0.22). Finally no differences in total (185.5 35.2 vs 175.0 47.3 mg/dl), HDL cholesterol (46.2 11.0 vs 45.2 10.8 mg/dl), tryglicerides (157.0 78.7 vs 138.2 48.2 mg/dl), ALT (22.6 8.3 vs 19.5 6.5 U/l) and AST (32.2 19.1 vs 26.2 12.0) values has been observed.
4.
e19
Discussion
In this study we demonstrated that type 2 diabetes patients switched from NPH to detemir had improved metabolic control and reduced waist circumference after 20 weeks. Moreover patients reported an improvement in treatment satisfaction using the standardised DTSQ. As shown HbA1c value was reduced after insulin detemir treatment, despite no significant increase in the insulin or OAD dose. This effect could be explained by a better adherence to diet. However it remains to investigate whether detemir was able to reduce food intake. In addition to benefits of glycemic control and tolerability [10] detemir has, uniquely, been reported to result in less weight gain compared with other basal insulins such as NPH and glargine [14,15]. Our data support this finding, as weight change was negligible throughout the study despite the improvement in glycemic control. The effect seen on waist circumference was investigated for the first time in this population and it is of interest because high waist circumference, due to visceral fat deposition, represents one component of metabolic syndrome. In patients with type 2 diabetes, metabolic syndrome is thought to associate with increased cardiovascular risk [6]. Since the interplay of contributory factors are still poorly understood [7], metabolic syndrome is currently treated by addressing each component factor; further research is needed to determine whether detemir has the potential to influence cardiovascular risk via its reduced propensity for causing weight gain in comparison with alternative insulins.
Conflict of interest The authors state that they have no conflict of interest.
references
[1] 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 (UKPD33), Lancet 352 (1998) 837–853. [2] D.M. Nathan, J.B. Buse, M.B. Davidson, E. Ferrannini, R.R. Holman, R. Sherwin, et al., Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes, Diabetologia 49 (2006) 1711–1721. [3] R.R. Holman, K.I. Thorne, A.J. Farmer, M.J. Davies, J.F. Keenan, S. Paul, et al., Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes, N. Engl. J. Med. 357 (2007) 1716–1730. [4] M. Korytkowski, When oral agents fail: practical barriers to starting insulin, Int. J. Obes. 26 (2002) S18–24. [5] K. Bryden, A. Neil, R.A. Mayou, R.C. Peveler, C.G. Fairburn, D.B. Dunger, Eating habits, body weight and insulin misuse, Diabetes Care 22 (1999) 1959–1960. [6] E. Kozek, B. Katra, M. Malecki, J. Sieradzki, Visceral obesity and hemostatic profile in patients with type 2 diabetes: the
e20
[7]
[8] [9]
[10] [11]
[12]
diabetes research and clinical practice 84 (2009) e18–e20
effect of gender and metabolic compensation, Rev. Diabet. Stud. 1 (2004) 122–128. J. Wang, S. Ruotsalainen, L. Moilanen, P. Lepisto, M. Laakso, J. Kuusisto, The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns, Eur. Heart J. 28 (2007) 857–865. P. Kurtzhals, Pharmacology of insulin detemir, Endocrinol. Metab. Clin. North. Am. 36 (Suppl. 1) (2007) 14–20. A. Dornhorst, H.J. Lu¨ddeke, S. Sreenan, P. Kozlovski, J.B. Hansen, B.J. Looij, et al., Insulin detemir improves glycaemic control without weight gain in insulin-naı¨ve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE(TM) study, Int. J. Clin. Pract. 62 (2008) 659–665. T.M. Chapman, C.M. Perry, Spotlight on insulin detemir in type 1 and 2 diabetes mellitus, BioDrugs 19 (2005) 67–69. P. Home, P. Kurzhals, Insulin detemir: from concept to clinical experience, Expert Opin. Pharmacother. 7 (2006) 325–343. A. Dornhorst, H.-J. Lu¨ddeke, S. Sreenan, C. Koenen, J.B. Hansen, A. Tsur, et al., Safety and efficacy of insulin
detemir in clinical practice: 14-week follow-up data from type 1 and type 2 diabetes patients in the PREDICTIVETM European cohort, Int. J. Clin. Pract. 61 (2007) 523–528. [13] A. Dornhorst, H.J. Lu¨ddeke, C. Koenen, M. Merila¨inen, A. King, A. Robinson, et al., Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE, Diabetes Obes. Metab. 10 (2008) 75–81. [14] K. Hermansen, M. Davies, Does insulin detemir have a role in reducing risk of insulin-associated weight gain? Diabetes Obes. Metab. 9 (2007) 209–217. [15] J. Rosenstock, M. Davies, P.D. Home, J. Larsen, C. Koenen, G. Shernthaner, A randomized, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when added to glucose-lowering drugs in insulin-naive people with type 2 diabetes, Diabetologia 51 (2008) 408–416.